Heterocyclic benzenesulphonamide compounds as bradykinine antagonists

ABSTRACT

The invention concerns compounds selected among the group consisting of (i) compounds of formula (I) wherein: Het1 represents a nitrogenous heterocycle with 5 apices, in particular imidazole, pyrazole, or triazole; Het2 represents a nitrogenous heterocycle with 4, 5 or 6 apices, selected among the heterocycles: (II) wherein R 1  and R 2  are defined as mentioned in the description; and (ii) their additive salts. The invention also concerns the method for preparing said compounds and their use in therapy, in particular for treating pathologies involving bradykinine.

This application is a 371 of PCT/FR00/00398 filed Feb. 17, 2000, now WO00/50418.

FIELD OF THE INVENTION

The present invention relates to novel benzenesulphonamide compounds,their method of preparation and their therapeutic use.

These novel compounds have an antagonist action towards bradykinin andare useful in therapeutics, particularly for the treatment of pain andinflammation, and especially in the treatment of asthma, cerebraltraumatic shock and allergic rhinitis.

PRIOR ART

It is known that one of the possibilities for treatment of certainpathologies of painful and/or inflammatory character (such as asthma,rhinitis, septic shock, dental pain, etc.) is to inhibit the action ofcertain hormones such as bradykinin or kallidin. In reality, thesepeptide hormones are involved in a large number of physiologicalprocesses, some of which are closely associated with these pathologies.

Although at present no product having this mode of action iscommercially available yet, many studies have been undertaken in orderto understand the mode of action of kinins and in particular ofbradykinin and its homologues, then to create compounds capable of beingbradykinin-receptor antagonists. Among the numerous publicationsrelating to these studies, mention may be made of PharmacologicalReviews Vol. 44 no. 1, pages 1-80 (1992) and Biopolymers (PeptideScience) vol. 37 pages 143-155 (1995).

Bradykinin is a peptide hormone formed of 9 amino acids(Arg-Pro-Pro-Gly-Phe-Ser-Pro-Phe-Arg) and kallidin is a peptide hormone(Lys-Arg-Pro-Pro-Gly-Phe-Ser-Pro-Phe-Arg) which contains a supplementaryamino acid (Lys) with respect to bradykinin. It is known that priorstudies have made it possible to obtain peptides which interact with thebradykinin receptors: some such as bradycor (CP.0127 from the companyCortech), icatibant (HOE 140 from the company Hoechst) [“bradycor” and“icatibant” are international non-proprietary names (INN)] oralternatively NPC 17761 (from the company Scios-Nova) have an inhibitoryaction on the binding of bradykinin to its B₂ receptor. Recentpublications cite other peptides capable of having abradykinin-antagonist action towards its B₂ receptor; among these it ispossible to mention, for example, WO-A-97/09347, WO-A-97/09346, U.S.Pat. Nos. 5,610,140, 5,620,958, 5,610,142 and 5,597,803. In addition,non-peptide compounds have been proposed as antagonists towards thebinding of bradykinin to its B₂ receptor, especially in EP-A-0596406,EP-A-0622361, U.S. Pat. Nos. 5,578,601, 5,510,380, FR-A-2735128,JP-A-09/040662, FR-A-2737892, WO-A-97/11069, WO-A-97/41104,WO-A-96/13485 and FR-A-2765222. It is additionally known that certaincompounds of structure which is more or less related to those of thecompounds aimed at in the present application have already beendescribed, especially in DE-A-3617183 and EP-A-0261539, with regard totheir possible antithrombotic properties.

AIM OF THE INVENTION

There is a need to attenuate or to suppress pain and inflammation inmammals and especially in man.

To satisfy this need, a novel technical solution has been sought whichis effective in the treatment of pain irrespective of its origin,especially in the treatment of pain associated with inflammatory ortraumatic phenomena.

According to the invention, it is proposed to provide a novel technicalsolution, which employs, at the level of the bradykinin B₂ receptor,competitive binding between (i) bradykinin and related or analogoushormones, and (ii) an antagonist substance, and which requires compoundsof benzenesulphonamide type, which are structurally different from theabovementioned known products, and are capable of limiting orsubstantially inhibiting the binding of bradykinin and analogoushormones to the said bradykinin B₂ receptor.

According to this technical solution, the novel compounds bindcompetitively to the bradykinin B₂ receptor without causing the effectsof bradykinin on this receptor (these novel compounds are so-calledantagonist substances). This results in the appearance of a stateanalogous to that observed in the absence of bradykinin, namely adecrease in pain, inflammatory reactions and other harmful effectscaused by the receptors activated by bradykinin.

In accordance with this novel technical solution, according to a firstaspect of the invention, compounds derived from benzenesulphonamide areproposed as novel industrial products; according to a second aspect ofthe invention, a method of preparation of these compounds is proposed;and according to a third aspect of the invention, a use of thesecompounds, especially a therapeutic use, as active principles ofspecialities or medicinal compositions is proposed.

SUBJECT OF THE INVENTION

According to the novel technical solution of the invention, abenzenesulphonamide compound is recommended as novel industrial product,which is characterized in that it is chosen from the group formed by:

(i) the compounds of formula I:

 in which:

Het1 represents a 5-membered nitrogen-containing heterocycle, especiallyimidazole, pyrazole or triazole,

Het2 represents a 4-, 5- or 6-membered nitrogen-containing heterocycleof structure:

 in which

R₁ represents a hydrogen atom or a hydroxyl, C₁-C₄ alkoxy, phenoxy,phenylmethoxy, —CH₂OH, cycloalkyloxy, cycloalkylalkoxy (where eachcycloalkyl fragment is C₃-C₈ and the alkoxy fragment is C₁-C₄),—NH—CO—CH₃, —CO—NH₂ or —CO—NH—CH₃ group,

R₂ represents a hydrogen atom or a —CH₂OH, —CH₂—O—CH₃, —CONR₃R₄,

R₃ represents a hydrogen atom, a C₁-C₃ alkyl group, a C₃-C₈ cycloalkylgroup, a (C₃-C₈) cycloalkyl (C₁—C₃) alkyl group, a phenyl group, or aphenylmethyl group,

R₄ represents a hydrogen atom, a C₁-C₃ alkyl, —(CH₂)n—CH₂OH,—(CH₂)n—COOH, —(CH₂)n—CH₂—NR₅R₆,

R₅ represents a hydrogen atom, a C₁-C₃ alkyl, phenyl, phenylmethyl,pyridinyl, pyridinylmethyl, pyridinylethyl, benzoyl,4-(amino-iminomethyl)benzoyl, —(CH₂)_(m)—CH₂OH, —(CH₂)_(m)—COOH,—(CH₂)_(m)CH₂—O—(CH₂)_(m)—CH₂OH, —CO—(CH₂)_(m)—COOH, or

R₆ represents a hydrogen atom or a C₁-C₃ alkyl group, or, R₅ and R₆considered together form, with the nitrogen atom to which they areattached, a 5- to 6-membered N heterocycle,

n=1, 2, 3 or 4,

m=1, 2 or 3; and

(ii) their addition salts.

According to the invention, a method of preparation of the compounds offormula I and their addition salts is also recommended.

The use of a bradykinin B₂ receptor antagonist substance, chosen fromthe compounds of formula I of the present invention and their non-toxicaddition salts, is likewise recommended for obtaining a medicamentintended for human or animal therapeutic use, against pathologiesinvolving bradykinin or its homologues, in particular against pain,especially in the treatment or prevention of pathologies associated withinflammatory or painful states, and against severe traumatic shock, inparticular cerebral traumatic shock.

DETAILED DESCRIPTION OF THE INVENTION

In the general formula I of the compounds of the invention, C₁-C₃ alkylgroup is understood as meaning a methyl, ethyl, propyl or 1-methylethylgroup.

C₁-C₄ alkoxy group is preferentially understood here as meaning themethoxy, ethoxy, propoxy, butoxy, 1-methylethoxy and 1,1-dimethylethoxygroups. C₃-C₈ cycloalkyl group is understood as meaning the cyclopropyl,cyclobutyl, cyclopentyl, cyclohexyl groups, and (cycloalkyl)alkyl groupsare understood as meaning especially the cyclopropylmethyl,cyclopropylethyl, cyclohexylmethyl and cyclohexylethyl groups.

When a group such as R₅ comprises a heterocycle, for example pyridine,and the position of substitution is not specified, it must be understoodthat the bond with the heterocycle can be made with any of thesubstitutable members.

5- to 6-membered NR₅R₆ heterocycle is understood as meaning apyrrolidine, piperidine, piperazine or morpholine ring, and moreparticularly a 1-pyrrolidinyl, 1-piperidinyl, 1-piperazinyl or1-morpholinyl group.

The heterocycle Het1, which has five members, comprises one or moreheteroatoms. Advantageously, it comprises 1 to 4 nitrogen members. Asrepresented by the formula I above, Het1 is linked by its nitrogenmember or one of its nitrogen members to position 4 of the quinoline.

The heterocycle Het2 is linked by its nitrogen member to the sulphuratom of the group SO₂ to form the sulphonamide function.

When, on the heterocycle Het2, the substituent R₂ is not a hydrogenatom, the carbon of the ring which carries the substituent R₂ can havean S or R configuration. In this case, the compounds according to theinvention can be of indeterminate configuration (that is to say amixture of the R and S isomers) or, preferably, one of the R or Sisomers, or, preferentially, the S isomer. In the same way, thesubstituent R₁, when it is not hydrogen, introduces an asymmetric centreand can be found in an indeterminate configuration, or determined R or Sconfiguration, the “trans” configuration with respect to the R₂ groupbeing preferred.

“Addition salts” are understood as meaning the acid addition saltsobtained by reaction of a compound of formula I in its non-salified formwith an inorganic acid or an organic acid. The inorganic acids preferredfor salifying a basic compound of formula I are hydrochloric,hydrobromic, phosphoric and sulphuric acids. The organic acids preferredfor salifying a basic compound of formula I are methanesulphonic,benzenesulphonic, maleic, fumaric, oxalic, citric, lactic, tartaric andtrifluoroacetic acids.

Among the compounds according to the present invention, those arepreferred in which the heterocycle Het1 is a 1-(1H)-imidazolyl group.The compounds are likewise preferred in which the heterocycle Het2comprises a 2(S)-pyrrolidinecarboxamide group,

and more particularly when

R₃ represents a hydrogen atom or a C₁-C₃ alkyl group, and

R₄ represents a C₁-C₃ alkyl group, a —(CH₂)_(n)—CH₂—NR₅R₆ group, apyridinylmethyl group or a

 group, and

R₅ represents a C₁-C₃ alkyl group, a —(CH₂)_(m)—CH₂OH group, a(2-pyridinyl)methyl group or a 4-(aminoiminomethyl)benzoyl group,

R₆ represents a methyl group or forms, with R₅ and the nitrogen to whichthey are bonded, a 5- or 6-membered saturated heterocycle.

“Ambient temperature” is understood as meaning a temperature of theorder of 15 to 25° C., and “temperature close to ambient temperature” asmeaning a temperature of approximately 0 to 40° C.

A general method of preparation of the compounds of the formula I, whichis recommended according to the invention, comprises: according to afirst variant A, the steps consisting of:

(1) reacting an 8-hydroxyquinoline derivative of formula II:

 in which:

Het1 represents a five-membered nitrogen-containing heterocyclecomprising in total 1, 2, 3 or 4 nitrogen atoms and M represents analkali metal, especially sodium or potassium,

with a compound of formula III:

 in which:

X represents a halogen atom, preferably a bromine atom, and

R₁ represents a hydrogen atom or an OH group, an alkoxy group or aphenoxy group,

in an anhydrous solvent such as, for example, dimethylformamide, at atemperature of between 0 and 50° C., for 0.5 to 10 hours, in order toobtain a compound of formula IV:

 in which:

Het1 and R₁ retain the same meaning as previously;

(2) hydrolysing the ester function of the compound of formula IV thusobtained according to step (1) above, especially by reaction with anaqueous solution of sodium hydroxide, in a miscible solvent such as, forexample, dioxane, at a temperature of the order of 20 to 60° C. and for1 to 5 hours, in order to obtain, after acidification, a compound offormula V:

 in which:

Het1 and R₁ retain the same meaning as above;

(3) reacting the compound of formula V thus obtained with an amine offormula:

HNR₃R₄  (VI)

 in which:

R₃ represents a hydrogen atom or a C₁-C₃ alkyl group,

R₄ represents a hydrogen atom, a C₁-C₃ alkyl, —(CH₂)_(n)—CH₂OH,—(CH₂)_(n)—COOR₁₁, —(CH₂)_(n)—CH₂—NR₅R₆,

R₅ represents a C₁-C₃ alkyl, —(CH₂)_(m)—CH₂OH, —(CH₂)_(m)—COOR₁₁,—(CH₂)_(m)—CH₂—O—(CH₂)_(m)—CH₂OH group, or an amino-protecting groupsuch as, for example, a 1,1-dimethylethoxycarbonyl (BOC) group, (R₅ andR₆ not simultaneously being amino-protecting groups),

R₆ represents a C₁-C₃ alkyl group or an amino-protecting group, forexample of the BOC type,

R₁₁ represents a protecting group of the acid function, which is easilyhydrolysable such as, for example, the t-butyl (or 1,1-dimethylethyl)group,

n=1, 2, 3 or 4,

m=1, 2 or 3,

in an appropriate solvent, in particular dichloromethane, in thepresence of activators such as, in particular,1-hydroxy-7-azabenzotriazole (HOAT) and1-[3-(dimethylaminopropyl)-3-ethy]carbodiimide hydrochloride (EDCI), ata temperature close to ambient temperature (0-40° C., preferably 10-35°C.), for 2 to 50 hours, in order to obtain a compound of formula:

 in which

Het1, R₁, R₃, R₄ keep the same meaning as previously; and

(4) if necessary, reacting the compound of formula VII thus obtained inorder to remove the amino- or acido-protecting groups in such a way asto replace these groups by a hydrogen atom, for example by reaction ofthe said compound VII with trifluoroacetic acid in order to remove anamino-protecting group of the BOC type or in order to remove anacido-protecting group of the t-butyl type, in such a way as to obtainthe compound of formula I:

 in which:

Het1, R₁, R₃ and R₄ keep the same meaning as above, with the exceptionof the protecting groups replaced by hydrogen atoms; then,

(5) if necessary, reacting the compound of formula I thus obtained withan acid in order to obtain the corresponding acid addition salt;

according to a second variant B consisting of:

(1) reacting a compound of formula I such as obtained in step (4) ofvariant A above,

 in which:

Het1 represents a 1-imidazolyl group, a 1-pyrazolyl group or a1-(1,2,4-triazolyl) group,

R₃ represents H, or a C₁-C₃ alkyl group,

R₄ represents a group which carries a primary or secondary aminefunction chosen from: —(CH₂)_(n)—CH₂—NHR₆ or

where R₆ represents H or an alkyl group and n represents 1, 2, 3 or 4,with a halogenated compound of formula: Y—(CH₂)_(m)—CH₂OR₁₃,Y—(CH₂)_(m)—COOR₁₁, or Y—(CH₂)_(m)—CH₂—O—(CH₂)_(m)—CH₂OR₁₃,

where

Y is a halogen, preferentially Br or I,

m represents 1, 2 or 3

R₁₁ is an acido-protecting group, such as, for example, t-butyl, and

R₁₃ is a protecting group of the alcohol function, in particular theacetyl group,

in a solvent such as, for example, dimethylformamide or acetonitrile, inthe presence of an agent with alkaline character, such as, for example,potassium carbonate, at a temperature close to ambient temperature andfor 5 to 20 hours, in order to obtain the compound of formula VII:

 in which:

R₃ represents H or a C₁-C₃ alkyl group,

R₄ represents a —(CH₂)_(n)—CH₂—NR₅R₆ or

 group where

R₅ represents group: —(CH₂)_(m)—CH₂OR₁₃, —(CH₂)_(m)—COOR₁₁, or—(CH₂)_(m)—CH₂—O—(CH₂)_(m)—CH₂OR₁₃,

Het1, R₆, R₁₁ and R₁₃ keep the same meaning as above;

(2) carrying out a deprotection reaction of each alcohol or acid groupin order to replace the R₁₃ and R₁₁ groups by a hydrogen atom, and tothus obtain the corresponding compounds of formula I;

(3) if necessary, reacting the compound of formula I thus obtained withan inorganic or organic acid in order to obtain the corresponding salt;

according to a third variant C, the steps consisting of:

(1) reacting the acid chloride of formula VIII:

 in which:

X represents a halogen, preferentially bromine,

with a heterocyclic derivative corresponding to the formula:

 where:

R₁ represents H, OH, alkoxy, phenoxy, phenylmethoxy, CH₂OH, C₃-C₈cycloalkyloxy or cycloalkylalkoxy where the cycloalkyl fragment is C₃-C₈and the alkoxy fragment C₁-C₄,

R₂ represents H, or a —CH₂OH, —CH₂OCH₃, —CONH(CH₂)_(n)CH₂NR₅R₁₂,—CONH(CH₂)_(n)CH₂OH, —CONH(CH₂)_(n)COOR₁₁ or

n=1, 2, 3 or 4,

R₅ represents H or an alkyl group,

R₁₁ represents an acido-protecting group, and

R₁₂ represents an amino-protecting group,

in a solvent such as, for example, acetonitrile, in the presence of abase such as, for example, potassium carbonate or triethylamine, at atemperature close to ambient temperature, for 10 to 30 hours, in orderto obtain a compound of formula IX:

 in which:

Het2 represents a

 group,

and X, R₁, R₂, R₁₁, R₁₂ and n keep the same meaning as above;

(2) reacting the compound of formula IX thus obtained with an8-hydroxy-quinoline derivative of formula II:

 in which:

Het1 represents a 5-membered nitrogen-containing heterocycle comprising1, 2, 3 or 4 nitrogen atoms and M represents an alkali metal, inparticular sodium or potassium,

under conditions analogous to those employed in step (1) of thepreceding variant A, in order to obtain a compound of formula X:

 in which:

Het1 and Het2 retain the same meaning as above;

(3) if necessary, carrying out a deprotection reaction, for example bythe action of trifluoroacetic acid, in order to replace each R₁₁, or R₁₂protecting group of the acid or amine functions by a hydrogen atom, inorder to obtain a compound of formula I:

 in which:

Het1 retains the same meaning as above, and

Het2 represents a

R₁ has the same meaning as above,

R₂ represents a —CH₂OH, —CH₂OCH₃, —CONH(CH₂)_(n)CH₂NHR₅,CONH(CH₂)_(n)CH₂OH, —CONH(CH₂)_(n)COOH or

n=1, 2, 3 or 4, and

R₅ represents H or an alkyl group; and

(4) if necessary, reacting the compound of formula I thus obtained withan acid in order to obtain the corresponding salt.

The invention will be better understood on reading (i) examples ofpreparation and (ii) results of pharmacological tests carried out withthe compounds according to the invention, which will follow. Of course,both these elements together are not limiting but are given by way ofillustration.

In the case of compounds having an asymmetric carbon in their structure,the absence of particular indication or the comment (R,S) signifies thatracemic compounds are concerned; in the case of compounds havingchirality, this is indicated immediately following the indexation of thesubstituent carried by the said asymmetric carbon; the (R) or (S) signsare then used, in accordance with the Cahn, Ingold and Prelog rules. Thenomenclature used in the examples is that recommended by ChemicalAbstracts: thus certain derivatives of L-proline can become, afterreaction of the acid function with an amine, derivatives of2(S)-pyrrolidinecarboxamide.

Preparation I1-[[2,4-Dichloro-3-[[[4-(1H-imidazol-1-yl)-2-methyl-8-quinolinyl]oxy]methyl]-phenyl]sulphonyl]-L-proline,methyl ester

A solution of 0.7 g (3.11×10⁻³ mol) of8-hydroxy-4-[1H-imidazol-1-yl]-2-methylquinoline is prepared in 20 ml ofdimethylformamide (DMF) and 0.11 g (3.42×10⁻³ mol) of 75% sodium hydridein oil is added. After 10 minutes with stirring at ambient temperature,1.47 g (3.42×10⁻³ mol) of the methyl ester ofN-[3-(bromomethyl)-2,4-dichlorophenylsulphonyl]-L-proline are added.After 15 hours with stirring at ambient temperature, the reactionmixture is hydrolysed on iced water and extracted with ethyl acetate.The organic phase is washed with water, dried over magnesium sulphateand then concentrated under reduced pressure. The residue obtained ispurified by chromatography on silica gel eluting with the aid of atoluene/propanol mixture (95/5; v/v). 1.07 g of the expected product arethus obtained in the form of a beige solid (yield=68%).

M.p.=100° C.

[α]²⁷ _(D)=−14.4° (c=0.33; CH₃OH)

Preparation II1-[[2,4-Dichloro-3-[[[4-(1H-imidazol-1-yl)-2-methyl-8-quinolinyl]oxy]methyl]-phenyl]sulphonyl]-L-proline

1.6 ml (1.6×10⁻³ mol) of a normal solution of sodium hydroxide in waterare added to a solution of 0.44 g (0.763×10⁻³ mol) of the compoundobtained according to Preparation I in 30 ml of dioxane. The reactionmixture is heated to gentle reflux for 8 hours and the solvent is thendriven off under reduced pressure. The residue is taken up again inwater and the solution is gently acidified to pH 4.5 with the aid of asolution of hydrochloric acid. The expected acid precipitates. Theprecipitate is filtered, washed with water on the filter and dried at40° C. under reduced pressure. 0.36 g of the expected product is thusobtained in the form of white powder (Yield=89%).

M.p.=172° C.

EXAMPLE 11-[[2,4-Dichloro-3-[[[4-(1H-imidazol-1-yl)-2-methyl-8-quinolyl]oxy]methyl]-phenyl]sulphonyl]-N-methyl-2-(S)-pyrrolidinecarboxamide

A solution of 0.35 g (0.633×10⁻³ mol) of acid obtained according toPreparation II is prepared in 25 ml of dichloromethane and 0.13 g(0.686×10⁻³ mol) of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimidehydrochloride (EDCl), 0.1 g (0.686×10⁻³ mol) of1-hydroxy-7-azabenzotriazole (HOAT), 0.138 g (1.37×10⁻³ mol) oftriethylamine, then 0.05 g (0.748×10⁻³ mol) of methylamine hydrochlorideare added. The reaction mixture is stirred at ambient temperature for 20hours. It is then hydrolysed in cold water and extracted withdichloromethane. The organic phase is dried over magnesium sulphate andthen concentrated under reduced pressure. The residue is purified bychromatography on silica gel eluting with the aid of adichloromethane/methanol (98/2; v/v) mixture. 0.29 g of the expectedproduct is thus obtained in the form of an ecru solid (yield=81%).

M.p.=90° C.

[α]²⁷ _(D)=−28° (c=0.46; CH₃OH)

EXAMPLE 21-[[2,4-Dichloro-3-[[[4-(1H-imidazol-1-yl)-2-methyl-8-quinolyl]oxy]methyl]-phenyl]sulphonyl]-N-methyl-2-(S)-pyrrolidinecarboxamide,tartrate

A solution of 0.28 g (0.487×10⁻³ mol) of the compound obtained accordingto Example 1 is prepared in 3 ml of methanol and 0.073 g (0.487×10⁻³mol) of L-tartaric acid is added. The reaction mixture is kept withstirring at ambient temperature for 10 minutes and then concentratedunder reduced pressure. The residue is redissolved in 10 ml of distilledwater and the solution obtained is lyophilized. 0.34 g of the expectedsalt is thus obtained in the form of a fine and light white solid(Yield=96%).

M.p.=119° C.

[α]²⁷ _(D)=−19° (c=0.45; CH₃OH)

Preparation III N-(3-Aminopropyl)-4-cyanobenzamide, trifluoroacetate

A solution of 51 g (0.168 mol) of[3-[(4-cyanobenzoyl)amino]-propyl]carbamic acid, 1,1-dimethylethyl esteris prepared in 300 ml of dichloromethane and 25 ml of trifluoroaceticacid are added, at 0° C., with stirring. The reaction mixture is broughtback to ambient temperature and kept for 4 hours with stirring. Themixture is concentrated under reduced pressure and the residue is takenup in ethyl ether. The expected product crystallizes. It is filtered,washed with a little ethyl ether on the filter and dried under reducedpressure. 52 g of the product are thus obtained in the form of whitecrystals (Yield=97%).

M.p.=160° C.

Preparation IVN-[3-[(4-Cyanobenzoyl)amino]propyl]-1-[[2,4-dichloro-3-[[[4-(1H-imidazol-1-yl)-2-methyl-8-quinolinyl]oxy]methyl]phenyl]sulphonyl]-2(S)-pyrrolidine-carboxamide

Working analogously to Example 1, starting from the compounds obtainedaccording to Preparations II and III, the expected product is obtainedin the form of a beige solid (Yield=81%).

M.p.=118° C.

[α]²⁷ _(D)=−33.2° (c=0.32; CH₃OH)

Preparation VN-[3-[[4-[Amino(hydroxyimino)methyl]benzoyl]amino]propyl]-1-[[2,4-dichloro-3-[[[4-(1H-imidazol-1-yl)-2-methyl-8-quinolinyl]oxy]methyl]-phenyl]sulphonyl]-2(S)-pyrrolidinecarboxamide

A solution of 0.058 g (0.843×10⁻³ mol) of hydroxylamine hydrochloride isprepared in 2 ml of DMSO and 0.170 g (1.69×10⁻³ mol) of triethylamine,then 0.36 g (0.48×10⁻³ mol) of the compound obtained according toPreparation IV, are added. The reaction mixture is kept with stirring atambient temperature for 1 hour, and then the same quantity ofhydroxylamine hydrochloride and triethylamine is added again. After 15hours with stirring at ambient temperature, the reaction mixture ispoured onto water. The precipitate formed is separated by filtration,and then washed with water and dried under reduced pressure at 30° C.0.37 g of the expected product is thus obtained in the form of a whitepowder (Yield=98%).

M.p.=160° C.

[α]²⁷ _(D)=−22.5° (c=0.35; CH₃OH)

Preparation VIN-[3-[[4-[[(Acetyloxy)imino]aminomethyl]benzoyl]amino]propyl]-1-[[2,4-dichloro-3-[[[4-(1H-imidazol-1-yl)-2-methyl-8-quinolinyl]oxy]methyl]-phenyl]sulphonyl]-2(S)-pyrrolidinecarboxamide

A suspension of 0.32 g (0.41×10⁻³ mol) of the compound obtainedaccording to Preparation V is prepared in 10 ml of dichloromethane and0.134 g (1.23×10⁻³ mol) of acetic anhydride is added. The mixture isstirred for 3 hours at ambient temperature and then 0.134 g of aceticanhydride is added again and the mixture is stirred for 15 hours. Thereaction mixture is hydrolysed and extracted with dichloromethane. Theorganic phase is washed with water and then dried over magnesiumsulphate and concentrated under reduced pressure. 0.32 g of the expectedproduct is thus obtained in the form of a white solid (Yield=95%).

M.p.=96° C.

[α]²⁷ _(D)=−20.3° (c=0.32; CH₃OH)

EXAMPLE 3N-[3-[[4-(Aminoiminomethyl)benzoyl]amino]propyl]-1-[[2,4-dichloro-3-[[[4-(1H-imidazol-1-yl)-2-methyl-8-quinolinyl]oxy]methyl]phenyl]sulphonyl]-2(S)-pyrrolidinecarboxamide

A solution of 0.31 g (0.377×10⁻³ mol) of the compound obtained accordingto Preparation VI is prepared in 20 ml of methanol and 0.12 g of Lindlarcatalyst (with 5% of palladium) is added. The mixture is stirred under ahydrogen atmosphere at atmospheric pressure and ambient temperature for6 hours. The catalyst is removed by filtration and then the filtrate isconcentrated under reduced pressure. The residue is taken up with waterand the solution obtained is brought to a slightly alkaline pH with theaid of 1N sodium hydroxide. The white precipitate formed is filtered,washed with water and then dried under reduced pressure. Purification ofthis product is then carried out by chromatography on NH₂ grafted silicagel (Lichroprep® NH₂), eluting with the aid of adichloromethane/methanol (98/2; v/v) mixture. 0.19 g of the expectedproduct is thus obtained in the form of a yellow solid (Yield=66%).

M.p.=148° C.

[α]²⁷ _(D)=−28.3° (c=0.36; CH₃OH)

EXAMPLE 4N-[3-[[4-(Aminoiminomethyl)benzoyl]amino]propyl]-1-[[2,4-dichloro-3-[[[4-(1H-imidazol-1-yl)-2-methyl-8-quinolinyl]oxy]methyl]phenyl]sulphonyl]-2(S)-pyrrolidinecarboxamide,bis methanesulphonate

A solution of 0.17 g (0.22×10⁻³ mol) of the compound obtained accordingto Example 3 is prepared in 4 ml of methanol and 0.0428 g (0.44×10⁻³mol) of methanesulphonic acid is added. The reaction mixture is stirredfor 10 min at ambient temperature and then concentrated under reducedpressure. The residue is redissolved in distilled water; the solutionobtained is filtered and then lyophilized. 0.16 g of the expectedproduct is thus obtained in the form of a white fluffy solid(Yield=75%).

M.p.=176° C.

[α]²⁸ _(D)=−28.3° (c=0.32; CH₃OH)

Preparation VII1-[[3-(Bromomethyl)-2,4-dichlorophenyl]sulphonyl]-2(S)-pyrrolidinemethanol

A solution of 1 g (2.95×10⁻³ mol) of3-bromomethyl-2,4-dichlorobenzenesulphonyl chloride is prepared in 10 mlof acetonitrile and 4 ml of water. 292 μl (2.95×10⁻³ mol) ofL-(+)-prolinol and a solution of 886 mg of potassium carbonate in 4 mlof water are added. After 20 hours with stirring at ambient temperature,the reaction mixture is poured onto water and extracted with ethylacetate. The organic phase is washed with water, dried over magnesiumsulphate and concentrated under reduced pressure. 1.2 g of crude productare obtained which are purified by chromatography on silica gel elutingwith a toluene/ethyl acetate (80/20; v/v). mixture. 0.92 g of theexpected product is thus obtained in the form of a colourless oil(Yield=77%).

[α]²⁶ _(D)=−16.5° (c=0.5; CH₃OH)

EXAMPLE 51-[[2,4-Dichloro-3-[[[4-(1H-imidazol-1-yl)-2-methyl-8-quinolinyl]oxy]methyl]-phenyl]sulphonyl]-2(S)-pyrrolidinemethanol

Working analogously to Preparation I, starting from8-hydroxy-4-(1H-imidazol-1-yl)-2-methylquinoline and the compoundobtained according to Preparation VII, the expected product is obtainedin the form of white crystals (Yield=35%).

M.p.=76° C.

[α]²⁶ _(D)=−14.9° (c=0.8; CH₃OH)

EXAMPLE 61-[[2,4-Dichloro-3-[[[4-(1H-imidazol-1-yl)-2-methyl-8-quinolinyl]oxy]methyl]phenyl]sulphonyl]-2(S)-pyrrolidinemethanol,methanesulphonate

Working analogously to Example 4, starting from the compound obtainedaccording to Example 5 and from one molar equivalent of methanesulphonicacid, the expected product is obtained in the form of pale yellowcrystals (Yield=90%).

M.p.=134° C.

[α]²⁶ _(D)=+3.1° (c=0.84; CH₃OH)

EXAMPLE 71-[[2,4-Dichloro-3-[[[2-methyl-4-(1H-pyrazol-1-yl)-8-quinolinyl]oxy]methyl]-phenyl]sulphonyl]-2(S)-pyrrolidinemethanol

Working analogously to Example 5, starting from8-hydroxy-2-methyl-4-(1H-pyrazol-1-yl)quinoline, the expected product isobtained in the form of white crystals (Yield=77%).

M.p.=65° C.

[α]²⁶ _(D)=−14.9° (c=0.7; CH₃OH)

EXAMPLE 81-[[2,4-Dichloro-3-[[[2-methyl-4-(1H-pyrazol-1-yl)-8-quinolinyl]oxy]methyl]-phenyl]sulphonyl]-2(S)-pyrrolidinemethanol,methanesulphonate

Working analogously to Example 6, starting from the compound obtainedaccording to Example 7, the expected salt is obtained in the form ofyellow crystals (Yield=99%).

M.p.=120° C.

[α]²⁶ _(D)=+11.2° (c=0.75; CH₃OH)

Preparation VIII4-[[[[1-[(Phenylmethoxy)carbonyl]-2(S)-pyrrolidinyl]carbonyl]amino]methyl]-1-piperidinecarboxylicacid, 1,1-dimethylethyl ester

Working analogously to Example 1, starting fromN-[(phenyl-methoxy)carbonyl]-L-proline and4-(aminomethyl)-1-piperidinecarboxylic acid, 1,1-dimethylethyl ester,the expected product is obtained in the form of a creamy white solid(Yield=99%).

M.p.=50° C.

[α]²⁶ _(D)=−31° (c=0.80; CH₃OH)

Preparation IX4-[[[(2(S)-Pyrrolidinyl)carbonyl]amino]methyl]-1-piperidinecarboxylicacid, 1,1-dimethylethyl ester (acetate)

A solution of 100.9 g (0.23 mol) of the compound obtained according toPreparation VIII is prepared in acetic acid. Under a nitrogenatmosphere, 96.4 ml (1.02 mol) of cyclohexadiene, and then 2 g of 10%palladium on carbon are added. The reaction mixture is heated at refluxfor 5 hours. After cooling to 10-15° C., the reaction mixture isfiltered and concentrated under reduced pressure. The residue ispurified by chromatography on silica gel eluting with adichloromethane/ethanol (6/4; v/v) mixture. 60 g of the expected productare thus obtained in the form of an orange oil (Yield=72%, expressed assalt with acetic acid).

[α]²² _(D)=−36,8° (c=0.63; CH₃OH)

Preparation X4-[[[[1-[[3-(Bromomethyl)-2,4-dichlorophenyl]sulphonyl]-2(S)-pyrrolidinyl]-carbonyl]amino]methyl]-1-piperidinecarboxylicacid, 1,1-dimethylethyl ester

Working analogously to Preparation VII, starting from3-(bromomethyl)-2,4-dichlorobenzenesulphonyl chloride and the compoundobtained according to Preparation IX, the expected product is obtainedin the form of a white powder (Yield=97%).

M.p.=80° C.

[α]²² _(D)=−31° (c=0.92; CH₃OH)

Preparation XI4-[[[[1-[[2,4-Dichloro-3-[[[4-(1H-imidazol-1-yl)-2-methyl-8-quinolinyl]oxy]-methyl]phenyl]sulphonyl]-2(S)-pyrrolidinyl]carbonyl]amino]methyl]-1-piperidinecarboxylicacid, 1,1-dimethylethyl ester

Working analogously to Preparation I, starting from the compoundobtained according to Preparation X, the expected product is obtained inthe form of a creamy white solid (Yield=44%).

M.p.=100° C.

[α]²⁷ _(D)=−28.8° (c=0.36; CH₃OH)

EXAMPLE 91-[[2,4-Dichloro-3-[[[4-(1H-imidazol-1-yl)-2-methyl-8-quinolinyl]oxy]methyl]-phenyl]sulphonyl]-N-(4-piperidinylmethyl)-2(S)-pyrrolidinecarboxamide

A solution of 6 g (7.92×10⁻³ mol) of the compound obtained according toPreparation XI is prepared in 100 ml of dichloromethane and 0.856 g(7.92×10⁻³ mol) of anisole is added. The mixture is cooled to 0° C. and5 ml of trifluoroacetic acid are added. The solution is then stirred for15 hours at ambient temperature, and then concentrated under reducedpressure. The residue is taken up with water and the solution obtainedis brought to basic pH with a solution of normal sodium hydroxide. Themixture is extracted with ethyl acetate, and then the organic phase isdried over magnesium sulphate and concentrated. The crude product ispurified by chromatography on silica gel eluting with the aid of adichloromethane/methanol/ammonia (95/5/0.02; v/v/v) mixture. 4.4 g ofthe expected product are thus obtained in the form of a yellow solid(Yield=84%).

M.p.=150° C.

[α]²² _(D)=−47° (c=0.35; CH₃OH)

EXAMPLE 101-[[2,4-Dichloro-3-[[[4-(1H-imidazol-1-yl)-2-methyl-8-quinolinyl]oxy]methyl]-phenyl]sulphonyl]-N-(4-piperidinylmethyl)-2(S)-pyrrolidinecarboxamide,ditartrate

Working analogously to Example 2, starting from the compound obtainedaccording to Example 9 and using 2 mol of tartaric acid per mole of thesaid compound, the expected product is obtained in the form of a whitefluffy solid (Yield=81%).

M.p.=145° C.

[α]²⁷ _(D)=−23.7° (c=0.31; CH₃OH)

Preparation XII Acetic acid, 2-(2-iodoethoxy)ethyl ester

A solution of 2.4 g (14×10⁻³ mol) of 2-(2-chloroethoxy)ethyl acetate isprepared in 60 ml of acetone and 22 g (0.144 mol) of sodium iodide areadded. The reaction mixture is heated at reflux for 6 hours, and thenconcentrated under reduced pressure. The residue is taken up with waterand ethyl acetate. The organic phase is dried over magnesium sulphateand concentrated under reduced pressure. 2.81 g of the expected productare thus obtained, which is used without other purification, in the formof an orangey oil (Yield=78%).

n_(D)=1.468

Preparation XIII1-[[2,4-Dichloro-3-[[[4-(1H-imidazol-1-yl)-2-methyl-8-quinolinyl]oxy]methyl]-phenyl]sulphonyl]-N-[[1-[2-[2-(acetoxy)ethoxy]ethyl]-4-piperidinyl]methyl]-2(S)-pyrrolidinecarboxamide

A mixture of 0.3 g (0.456×10⁻³ mol) of the compound obtained accordingto Example 9 is prepared in 10 ml of acetonitrile and 4 ml ofdimethylformamide. 95 mg (0.68×10⁻³ mol) of potassium carbonate and then130 mg (0.5×10⁻³ mol) of the compound obtained according to PreparationXII are added dissolved in 2 ml of acetonitrile. The reaction mixture iskept with stirring at ambient temperature for 15 hours and thenconcentrated under reduced pressure. The residue is taken up withdichloromethane and the organic phase thus obtained is washed withwater, dried over magnesium sulphate and concentrated under reducedpressure. The crude product is purified by chromatography on silica geleluting with the aid of a dichloromethane/methanol/ammonia (9/1/0.02;v/v/v) mixture. 0.18 g of the expected product is thus obtained in theform of an ecru solid (Yield=50%).

M.p.=90° C.

[α]²⁵ _(D)=−35.8° (c=0.31; CH₃OH)

EXAMPLE 111-[[2,4-Dichloro-3-[[[4-(1H-imidazol-1-yl)-2-methyl-8-quinolinyl]oxy]methyl]-phenyl]sulphonyl]-N-[[1-[2-(2-hydroxyethoxy)ethyl]-4-piperidinyl]methyl]-2(S)-pyrrolidinecarboxamide

A solution of 0.17 g (0.216×10⁻³ mol) of the compound obtained accordingto Preparation XIII is prepared in 7 ml of methanol and 1 g ofAmberlite® IRA 400 resin (in OH⁻ form) is added. The reaction mixture isstirred at ambient temperature for 15 hours, and then filtered so as toremove the resin. After concentration of the filtrate under reducedpressure, 0.14 g of the expected product is obtained in the form of awhite powdery solid (Yield=88%).

M.p.=96° C.

[α]²⁵ _(D)=−38.5° (c=0.32; CH₃OH)

EXAMPLE 121-[[2,4-Dichloro-3-[[[4-(1H-imidazol-1-yl)-2-methyl-8-quinolinyl]oxy]methyl]-phenyl]sulphonyl]-N-[[1-[2-(2-hydroxyethoxy)ethyl]-4-piperidinyl]methyl]-2(S)-pyrrolidinecarboxamide,tartrate

Working analogously to Example 2, starting from the compound obtainedaccording to Example 11, the expected salt is obtained in the form of afluffy white product (Yield=99%).

M.p.=135° C.

[α]²⁵ _(D)=−38° (c=0.43; CH₃OH)

Preparation XIVN-[[1-[[2,4-Dichloro-3-[[[4-(1H-imidazol-1-yl)-2-methyl-8-quinolinyl]oxy]-methyl]phenyl]sulphonyl]-2(S)-pyrrolidinyl]carbonyl]glycine,1,1-dimethyl-ethyl ester

Working analogously to Example 1, starting from the compound obtainedaccording to Preparation II and 1,1-dimethylethyl glycinate, theexpected product is obtained in the form of a white solid (Yield=93%).

M.p.=110° C.

[α]²² _(D)=−49° (c=0.3; CH₃OH)

EXAMPLE 13N-[[1-[[2,4-Dichloro-3-[[[4-(1H-imidazol-1-yl)-2-methyl-8-quinolinyl]oxy]-methyl]phenyl]sulphonyl]-2(S)-pyrrolidinyl]carbonyl]glycine,trifluoroacetate

A mixture of 0.27 g (0.4×10⁻³ mol) of the compound obtained according toPreparation XIV is prepared in 5 ml of dichloromethane and 43 mg(0.4×10⁻³ mol) of anisole, and then, at 0° C., 1.5 ml of trifluoroaceticacid are added. The solution is stirred at 0° C. for 1 hour and then atambient temperature for 24 hours. The reaction mixture is thenconcentrated under reduced pressure and the residue is triturated withethyl ether. The solvent is removed with the soluble products and theresidue is redissolved in distilled water. The solution is filtered, andthen lyophilized. 0.285 g of the expected product is thus obtained inthe form of a yellowish fine solid (Yield=86%).

M.p.=132° C.

[α]²² _(D)=−9° (c=0.64; CH₃OH)

EXAMPLE 141-[[2,4-Dichloro-3-[[[4-(1H-imidazol-1-yl)-2-methyl-8-quinolinyl]oxy]methyl]-phenyl]sulphonyl]-N-[2-(dimethylamino)ethyl]-2(S)-pyrrolidinecarboxamide

Working analogously to Example 1, starting from the compound obtainedaccording to Preparation II and N,N-dimethylethylenediamine, theexpected product is obtained in the form of a beige powder (Yield=40%).

M.p.=88° C.

[α]²³ _(D)=−44° (c=0.37; CH₃OH)

EXAMPLE 151-[[2,4-Dichloro-3-[[[4-(1H-imidazol-1-yl)-2-methyl-8-quinolinyl]oxy]methyl]-phenyl]sulphonyl]-N-[2-(dimethylamino)ethyl]-2(S)-pyrrolidinecarboxamide,tartrate

Working analogously to Example 2, starting from the compound obtainedaccording to Example 14, the expected product is obtained in the form ofan off-white fluffy solid (Yield of 93%).

M.p.=132° C.

[α]²⁴ _(D)=−41° (c=0.58; CH₃OH)

EXAMPLE 161-[[2,4-Dichloro-3-[[[4-(1H-imidazol-1-yl)-2-methyl-8-quinolinyl]oxy]methyl]-phenyl]sulphonyl]-N-[3-(dimethylamino)propyl]-2(S)-pyrrolidinecarboxamide

Working analogously to Example 1, starting from the compound obtainedaccording to Preparation II and N,N-dimethyl-1,3-propanediamine, theexpected product is obtained in the form of a white solid (Yield=40%).

M.p.=80° C.

[α]²⁴ _(D)=−47° (c=0.33; CH₃OH)

EXAMPLE 171-[[2,4-Dichloro-3-[[[4-(1H-imidazol-1-yl)-2-methyl-8-quinolinyl]oxy]methyl]-phenyl]sulphonyl]-N-[3-(dimethylamino)propyl]-2(S)-pyrrolidine-carboxamide,tartrate

Working analogously to Example 2, starting from the compound obtainedaccording to Example 16, the expected product is obtained in the form ofa white solid (Yield=87%).

M.p.=131° C.

[α]²⁴ _(D)=−43° (c=0.42; CH OH)

EXAMPLE 181-[[2,4-Dichloro-3-[[[4-(1H-imidazol-1-yl)-2-methyl-8-quinolinyl]oxy]methyl]-phenyl]sulphonyl]-N-[4-(dimethylaminobutyl]-2(S)-pyrrolidinecarboxamide

Working analogously to Example 1, starting from the compound obtainedaccording to Preparation II and N,N-dimethyl-1,4-butanediamine, theexpected product is obtained in the form of a white solid (Yield=51%).

M.p.=75° C.

[α]²² _(D)=−49° (c=0.31; CH₃OH)

EXAMPLE 191-[[2,4-Dichloro-3-[[[4-(1H-imidazol-1-yl)-2-methyl-8-quinolinyl]oxy]methyl]-phenyl]sulphonyl]-N-[4-(dimethylamino)butyl]-2(S)-pyrrolidinecarboxamide,tartrate

Working analogously to Example 2, starting from the compound obtainedaccording to Example 18, the expected product is obtained in the form ofa white fluffy solid (Yield=90%).

M.p.=125° C.

[α]²⁴ _(D)=−33° (c=0.35; CH₃OH)

EXAMPLE 201-[[2,4-Dichloro-3-[[[4-(1H-imidazol-1-yl)-2-methyl-8-quinolinyl]oxy]methyl]-phenyl]sulphonyl]-N-[(1-methyl-4-piperidinyl)methyl]-2(S)-pyrrolidine-carboxamide

A mixture of 0.6 g (0.677×10⁻³ mol) of the compound obtained accordingto Example 9 is prepared in 20 ml of dichloromethane and 0.15 g(1.49×10⁻³ mol) of triethylamine is added, and then 0.08 g ofparaformaldehyde and 0.37 g (27.1×10⁻³ mol) of zinc chloride. Thereaction mixture is kept with stirring for 1 hour, and then 0.1 g(2.64×10⁻³ mol) of sodium borohydride and 2 ml of methanol are added.Stirring at ambient temperature is continued for 15 hours and then themixture is concentrated under reduced pressure. The residue is taken upwith water and the aqueous phase thus obtained is brought to alkaline pHwith the aid of an ammonia solution and is extracted with ethyl acetate.The organic phase is dried and then concentrated under reduced pressure.The residue obtained is purified by chromatography on silica gel elutingwith a dichloromethane/methanol/ammonia (95/5/0.2; v/v/v) mixture. 0.25g of the expected product is thus obtained in the form of a white powder(Yield=55%).

M.p.=86° C.

[α]²⁷ _(D)=−36° (c=0.33; CH₃OH)

EXAMPLE 211-[[2,4-Dichloro-3-[[[4-(1H-imidazol-1-yl)-2-methyl-8-quinolinyl]oxy]methyl]-phenyl]sulphonyl]-N-[(1-methyl-4-piperidinyl)methyl]-2(S)-pyrrolidine-carboxamide,tartrate

Working analogously to Example 2, starting from the compound obtainedaccording to Example 20, the expected product is obtained in the form ofa white solid (Yield=97%).

M.p.=135° C.

[α]²⁷ _(D)=−34.3° (c=0.58; CH₃OH)

Preparation XV1-[[2,4-Dichloro-3-[[[4-(1H-imidazol-1-yl)-2-methyl-8-quinolinyl]oxy]methyl]-phenyl]sulphonyl]-N-[[1-[3-(acetoxy)propyl]-4-piperidinyl]methyl]-2(S)-pyrrolidinecarboxamide

Working analogously to Preparation XIII, starting from the compoundobtained according to Example 9 and 3-iodopropyl acetate, the expectedproduct is obtained (Yield=52%).

M.p.=96° C.

[α]²⁷ _(D)=−32.2° (c=0.30; CH₃OH)

EXAMPLE 221-[[2,4-Dichloro-3-[[[4-(1H-imidazol-1-yl)-2-methyl-8-quinolinyl]oxy]methyl]-phenyl]sulphonyl]-N-[[1-(3-hydroxypropyl)-4-piperidinyl]methyl]-2(S)-pyrrolidinecarboxamide

A solution of 0.13 g (0.167×10⁻³ mol) of the compound obtained accordingto Preparation XV is prepared in 5 ml of methanol. 1 ml of water and 50mg (0.385×10⁻³ mol) of potassium carbonate are added. The mixture isstirred for 15 hours at ambient temperature and then concentrated underreduced pressure. The residue is taken up again in dichloromethane andthe organic phase is washed with water and then dried over magnesiumsulphate and concentrated under reduced pressure. The crude product ispurified by chromatography on silica gel eluting with the aid of adichloromethane/methanol (98/2;v/v) mixture. 0.09 g of the expectedproduct is thus obtained in the form of a white fine solid (Yield=74%).

M.p.=90° C.

[α]^(27hd D)=−35.5° (c=0.35; CH₃OH)

EXAMPLE 231-[[2,4-Dichloro-3-[[[4-(1H-imidazol-1-yl)-2-methyl-8-quinolinyl]oxy]methyl]-phenyl]sulphonyl]-N-[[1-(3-hydroxypropyl)-4-piperidinyl]methyl]-2(S)-pyrrolidinecarboxamide,tartrate

Working analogously to Example 2, starting from the compound obtainedaccording to Example 22, the expected product is obtained in the form ofwhite powder (Yield=95%).

M.p.=145° C.

[α]²⁶ _(D)=−10.4° (c=0.32; CH₃OH)

Preparation XVI4-[[[[1-[[2,4-Dichloro-3-[[[4-(1H-imidazol-1-yl)-2-methyl-8-quinolinyl]oxy]-methyl]phenyl]sulphonyl]-2(S)-pyrrolidinyl]carbonyl]amino]methyl]-1-piperidineaceticacid, 1,1-dimethylethyl ester

A mixture of 0.45 g (0.684×10⁻³ mol) of the compound obtained accordingto Example 9 is prepared in 4 ml of dimethylformamide and 30 ml ofacetonitrile. 0.11 g (0.752×10⁻³ mol) of potassium carbonate is added,and then 0.133 g (0.684×10⁻³ mol) of t-butyl bromoacetate. The reactionmixture is kept with stirring at ambient temperature for 15 hours andthen concentrated under reduced pressure. The residue is taken up againin water and the precipitate formed is extracted with ethyl acetate. Theorganic phase is washed with water and then dried and concentrated underreduced pressure. The crude product is purified by chromatography onsilica gel eluting with the aid of a dichloromethane/methanol (98/2;v/v)mixture. 0.31 g of the expected product is thus obtained in the form ofan ecru white solid (Yield=60%).

M.p.=100° C.

[α]²³ _(D)=−40° (c=0.30; CH₃OH)

EXAMPLE 244-[[[[1-[[2,4-Dichloro-3-[[[4-(1H-imidazol-1-yl)-2-methyl-8-quinolinyl]oxy]-methyl]phenyl]sulphonyl]-2(S)-pyrrolidinyl]carbonyl]amino]methyl]-1-piperidineaceticacid, bis trifluoroacetate

Working analogously to Example 13, starting from the compound obtainedaccording to Preparation XVI, the expected product is obtained in theform of a yellow light solid (Yield=90%).

M.p.=149° C.

[α]²¹ _(D)=−41° (c=0.40; CH₃OH)

Preparation XVII1-[[2,4-Dichloro-3-[[[2-methyl-4-(1H-pyrazol-1-yl)-8-quinolinyl]oxy]methyl]-phenyl]sulphonyl]-L-proline,methyl ester

Working analogously to Preparation I, starting from8-hydroxy-4-(1H-pyrazol-1-yl)-2-methylquinoline, the expected product isobtained in the form of a white solid (Yield=96%).

M.p.=90° C.

[α]²⁵ _(D)=−19° (c=0.50; CHCl₃)

Preparation XVIII1-[[2,4-Dichloro-3-[[[2-methyl-4-(1H-pyrazol-1-yl)-8-quinolinyl]oxy]methyl]-phenyl]sulphonyl]-L-proline

Working analogously to Preparation II, starting from the compoundobtained according to Preparation XVII, the expected product is obtainedin the form of an ecru white powder (Yield=91%).

M.p.=148° C.

[α]²⁷ _(D)=+1° (c=0.40; DMSO)

Preparation XIX4-[[[[1-[[2,4-Dichloro-3-[[[2-methyl-4-(1H-pyrazol-1-yl)-8-quinolinyl]oxy]-methyl]phenyl]sulphonyl]-2(S)-pyrrolidinyl]carbonyl]amino]methyl]-1-piperidinecarboxylicacid, 1,1-dimethylethyl ester

Working analogously to Example 1, starting from the compound obtainedaccording to Preparation XVIII and the t-butyl ester of4-(aminomethyl)-1-piperidinecarboxylic acid, the expected product isobtained in the form of a white solid (Yield=52%).

M.p.=109° C.

[α]²⁵ _(D)=−45° (c=0.44; CHCl₃)

EXAMPLE 251-[[2,4-Dichloro-3-[[[2-methyl-4-(1H-pyrazol-1-yl)-8-quinolinyl]oxy]methyl]-phenyl]sulphonyl]-N-(4-piperidinylmethyl)-2(S)-pyrrolidinecarboxamide,bis trifluoroacetate

Working analogously to Example 13, starting from the compound obtainedaccording to Preparation XIX, the expected product is obtained in theform of a white solid (Yield=89%).

M.p.=125° C.

[α]²⁶ _(D)=−27° (c=0.30; CH₃OH)

Preparation XX4-[[[[1-[[2,4-Dichloro-3-[[[2-methyl-4-(1H-1,2,4-triazol-1-yl)-8-quinolinyl]oxy]-methyl]phenyl]sulphonyl]-2(S)-pyrrolidinyl]carbonyl]amino]methyl]-1-piperidinecarboxylicacid, 1,1-dimethylethyl ester

Working analogously to Preparation XI, starting from the compoundobtained according to Preparation X and8-hydroxy-2-methyl-4-(1H-1,2,4-triazol-1-yl)quinoline, the expectedproduct is obtained in the form of a beige powder (Yield=93%).

M.p.=94° C.

[α]²⁴ _(D)=−44° (c=0.57; CHCl₃)

EXAMPLE 261-[[2,4-Dichloro-3-[[[2-methyl-4-(1H-1,2,4-triazol-1-yl)-8-quinolinyl]oxy]-methyl]phenyl]sulphonyl]-N-(4-piperidinylmethyl)-2(S)-pyrrolidine-carboxamide,bis trifluoroacetate

Working analogously to Example 25, starting from the compound obtainedaccording to Preparation XX, the expected product is obtained in theform of a white-cream solid (Yield=89%).

M.p.=130° C.

[α]¹⁸ _(D)=−28° (c=0.63; CH₃OH)

Preparation XXI1-[[2,4-Dichloro-3-[[[2-methyl-4-(1H-pyrazol-1-yl)-8-quinolinyl]oxy]methyl]-phenyl]sulphonyl]-N-[[1-[3-(acetoxy)propyl]-4-piperidinyl]methyl]-2(S)-pyrrolidinecarboxamide

Working analogously to Preparation XV, starting from the compoundobtained according to Example 25 and 3-iodopropyl acetate, the expectedproduct is obtained in the form of a white solid (Yield=64%).

M.p.=89° C.

[α]²⁴ _(D)=−41° (c=0.60; CHCl₃)

EXAMPLE 271-[[2,4-Dichloro-3-[[[2-methyl-4-(1H-pyrazol-1-yl)-8-quinolinyl]oxy]methyl]-phenyl]sulphonyl]-N-[[1-(3-hydroxypropyl)-4-piperidinyl]methyl]-2(S)-pyrrolidinecarboxamide

Working analogously to Example 22, starting from the compound obtainedaccording to Preparation XXI, the expected product is obtained in theform of a white fine powder (Yield=95%).

M.p.=112° C.

[α]²⁴ _(D)=−42° (c=0.38; CHCl₃)

EXAMPLE 281-[[2,4-Dichloro-3-[[[2-methyl-4-(1H-pyrazol-1-yl)-8-quinolinyl]oxy]methyl]-phenyl]sulphonyl]-N-[[1-(3-hydroxypropyl)-4-piperidinyl]methyl]-2(S)-pyrrolidinecarboxamide,tartrate

Working analogously to Example 2, starting from the compound obtainedaccording to Example 27, the expected product is obtained in the form ofa white solid (Yield=99%).

M.p.=136° C.

[α]²² _(D)=−39° (c=0.50; CH₃OH)

Preparation XXII1-[[2,4-Dichloro-3-[[[2-methyl-4-(1H-1,2,4-triazol-1-yl)-8-quinolinyl]oxy]-methyl]phenyl]sulphonyl]-N-[[1-[3-(acetoxy)propyl]-4-piperidinyl]methyl]-2(S)-pyrrolidinecarboxamide

Working analogously to Preparation XV, starting from the compoundobtained according to Example 26 and 3-iodopropyl acetate, the expectedproduct is obtained in the form of a creamy white solid (Yield=47%).

M.p.=120° C.

[α]²⁶ _(D)=−61° (c=0.4; CHCl₃)

EXAMPLE 291-[[2,4-Dichloro-3-[[[2-methyl-4-(1H-1,2,4-triazol-1-yl)-8-quinolinyl]oxy]-methyl]phenyl]sulphonyl]-N-[[1-(3-hydroxypropyl)-4-piperidinyl]methyl]-2(S)-pyrrolidinecarboxamide

Working analogously to Example 22, starting from the compound obtainedaccording to Preparation XXII, the expected product is obtained in theform of a white powder (Yield=83%).

M.p.=136° C.

[α]²² _(D)=−48° (c=0.55; CHCl₃)

EXAMPLE 301-[[2,4-Dichloro-3-[[[2-methyl-4-(1H-1,2,4-triazol-1-yl)-8-quinolinyl]oxy]-methyl]phenyl]sulphonyl]-N-[[1-(3-hydroxypropyl)-4-piperidinyl]methyl]-2(S)-pyrrolidinecarboxamide,tartrate

Working analogously to Example 2, starting from the compound obtainedaccording to Example 29, the expected product is obtained in the form ofa white powder (Yield=98%).

M.p.=123° C.

[α]²³ _(D)=−43° (c=0.48; CH₃OH)

Preparation XXIII1-[[2,4-Dichloro-3-[[[4-(1H-imidazol-1-yl)-2-methyl-8-quinolinyl]oxy]methyl]-phenyl]sulphonyl]-N-[[1-[4-(acetoxy)butyl]-4-piperidinyl]methyl]-2(S)-pyrrolidinecarboxamide

Working analogously to Preparation XV, starting from the compoundobtained according to Example 9 and 4-iodobutyl acetate, the expectedproduct is obtained (Yield=63%).

M.p.=86° C.

[α]²² _(D)=−44° (c=0.86; CHCl₃)

EXAMPLE 311-[[2,4-Dichloro-3-[[[4-(1H-imidazol-1-yl)-2-methyl-8-quinolinyl]oxy]methyl]-phenyl]sulphonyl]-N-[[1-(4-hydroxybutyl)-4-piperidinyl]methyl]-2(S)-pyrrolidinecarboxamide

Working analogously to Example 11, starting from the compound obtainedaccording to Preparation XXIII, the expected product is obtained in theform of a white solid (Yield=96%).

M.p.=112° C.

[α]²² _(D)=−49° (c=0.78; CHCl₃)

EXAMPLE 321-[[2,4-Dichloro-3-[[[4-(1H-imidazol-1-yl)-2-methyl-8-quinolinyl]oxy]methyl]-phenyl]sulphonyl]-N-[[1-(4-hydroxybutyl)-4-piperidinyl]methyl]-2(S)-pyrrolidinecarboxamide,tartrate

Working analogously to Example 2, starting from the compound obtainedaccording to Example 31, the expected product is obtained in the form ofa white solid (Yield=96%).

M.p.=133° C.

[α]²² _(D)=−41° (c=0.82; CH₃OH)

Preparation XXIV4-[(3-Bromomethyl-2,4-dichlorophenyl)sulphonyl]morpholine

Working analogously to Preparation VII, starting from morpholine and3-bromomethyl-2,4-dichlorobenzenesulphonyl chloride, the expectedproduct is obtained in the form of a yellow solid (Yield=85%) (theproduct contains the chloromethylated analogue in part).

M.p.=128° C.

EXAMPLE 338-[[2,6-Dichloro-3-(4-morpholinylsulphonyl)phenyl]methoxy]-4-(1H-imidazol-1-yl)-2-methylquinoline

Working analogously to Preparation I, starting from the product obtainedaccording to Preparation XXIV and8-hydroxy-4-(1H-imidazol-1-yl)-2-methylquinoline, the expected productis obtained in the form of a beige solid (Yield=34%).

M.p.=148° C.

EXAMPLE 348-[[2,6-Dichloro-3-(4-morpholinylsulphonyl)phenyl]methoxy]-4-(1H-imidazol-1-yl)-2-methylquinoline,trifluoroacetate

Working analogously to Example 1, starting from trifluoroacetic acid andthe compound obtained according to Example 33, the expected product isobtained in the form of a cream colour light powder (Yield=98%).

M.p.=93° C.

EXAMPLE 358-[[2,6-Dichloro-3-(4-morpholinylsulphonyl)phenyl]methoxy]-2-methyl-4-(1H-pyrazol-1-yl)quinoline

Working analogously to Example 33, starting from8-hydroxy-4-(1H-pyrazol-1-yl)-2-methylquinoline, the expected product isobtained in the form of an off-white solid (Yield=83%).

M.p.=178° C.

EXAMPLE 368-[[2,6-Dichloro-3-(4-morpholinylsulphonyl)phenyl]methoxy]-2-methyl-4-(1H-pyrazol-1-yl)quinoline,trifluoroacetate

Working analogously to Example 34, starting from Example 35, theexpected product is obtained in the form of a white solid (Yield=89%).

M.p.=110° C.

Preparation XXV1-[(3-Bromomethyl-2,4-dichlorophenyl)sulphonyl]-4-(hydroxymethyl)-piperidine

Working analogously to Preparation XXIV, starting from4-(hydroxymethyl)piperidine, the expected product is obtained in theform of a white powder (Yield=88%).

M.p.=121° C.

EXAMPLE 371-[[2,4-Dichloro-3-[[[4-(1H-imidazol-1-yl)-2-methyl-8-quinolinyl]oxy]methyl]-phenyl]sulphonyl]-4-piperidinemethanol

Working analogously to Example 33, starting from the product obtainedaccording to Preparation XXV and8-hydroxy-4-(1H-imidazol-1-yl)-2-methylquinoline, the expected productis obtained in the form of a white solid (Yield=40%).

M.p.=100° C.

EXAMPLE 381-[[2,4-Dichloro-3-[[[4-(1H-imidazol-1-yl)-2-methyl-8-quinolinyl]oxy]methyl]-phenyl]sulphonyl]-4-piperidinemethanol,trifluoroacetate

Working analogously to Example 34, starting from the product obtainedaccording to Example 37, the expected product is obtained in the form ofa white powder (Yield=98%).

M.p. =109° C.

EXAMPLE 391-[[2,4-Dichloro-3-[[[2-methyl-4-(1H-pyrazol-1-yl)-8-quinolinyl]oxy]methyl]-phenyl]sulphonyl]-4-piperidinemethanol

Working analogously to Example 37, starting from the product obtainedaccording to Preparation XXV and8-hydroxy-2-methyl-4-(1H-pyrazol-1-yl)quinoline, the expected product isobtained in the form of a beige solid (Yield=74%).

M.p.=138° C.

EXAMPLE 401-[[2,4-Dichloro-3-[[[2-methyl-4-(1H-pyrazol-1-yl)-8-quinolinyl]oxy]methyl]-phenyl]sulphonyl]-4-piperidinemethanol,trifluoroacetate

Working analogously to Example 34, starting from the product obtainedaccording to Example 39, the expected product is obtained in the form ofa creamy white powder (Yield=98%).

M.p.=90° C.

Preparation XXVI1-[[2,4-Dichloro-3-[[[4-(1H-imidazol-1-yl)-2-methyl-8-quinolinyl]oxy]methyl]-phenyl]sulphonyl]-4(R)-hydroxy-L-proline,methyl ester

Working analogously to Preparation I, starting from the methyl ester ofN-[(3-bromomethyl-2,4-dichlorophenyl)sulphonyl]-4-(R)-hydroxy-(L)-proline,the expected product is obtained in the form of an ecru white solid(Yield=69%).

M.p.=78° C.

[α]²² _(D)=+1° (c=0.66; CH₃OH)

Preparation XXVII1-[[2,4-Dichloro-3-[[[4-(1H-imidazol-1-yl)-2-methyl-8-quinolinyl]oxy]methyl]-phenyl]sulphonyl]-4(R)-hydroxy-L-proline

Working analogously to Preparation II, starting from the productobtained according to Preparation XXVI, the expected product is obtainedin the form of a white solid (Yield=51%).

M.p.=140° C.

[α]²⁷ _(D)=+13° (c=0.38; CH₃OH)

Preparation XXVIII4-[[[[1-[[2,4-Dichloro-3-[[[4-(1H-imidazol-1-yl)-2-methyl-8-quinolinyl]oxy]-methyl]phenyl]sulphonyl]-4(R)-hydroxy-2(S)-pyrrolidinyl]carbonyl]amino]-methyl]-1-piperidinecarboxylicacid, 1,1-dimethylethyl ester

Working analogously to Example 1, starting from the acid obtainedaccording to Preparation XXVII and the t-butyl ester of4-(aminomethyl)piperidine-carboxylic acid, the expected product isobtained in the form of a white solid (Yield=65%).

M.p.=124° C.

[α]²⁴ _(D)=−6° (c=0.51; CH₃OH)

EXAMPLE 411-[[2,4-Dichloro-3-[[[4-(1H-imidazol-1-yl)-2-methyl-8-quinolinyl]oxy]methyl]-phenyl]sulphonyl]-4(R)-hydroxy-N-(4-piperidinemethyl)-2(S)-pyrrolidine-carboxamide

Working analogously to Example 9, starting from the compound obtainedaccording to Preparation XXVIII, the expected product is obtained in theform of a yellowish solid (Yield=80%).

M.p.=140° C.

[α]²⁷ _(D)=−3° (c=0.33; CH₃OH)

EXAMPLE 421-[[2,4-Dichloro-3-[[[4-(1H-imidazol-1-yl)-2-methyl-8-quinolinyl]oxy]methyl]-phenyl]sulphonyl]-4(R)-hydroxy-N-(4-piperidinemethyl)-2(S)-pyrrolidine-carboxamide,ditartrate

Working analogously to Example 2, starting from the compound obtainedaccording to Example 41 and two molar equivalents of tartaric acid, theexpected product is obtained in the form of a yellow light solid(Yield=50%).

M.p.=156° C.

[α]²⁷ _(D)=+30° (c=0.38; DMSO)

EXAMPLE 431-[[1,2,4-Dichloro-3-[[[4-(1H-imidazol-1-yl)-2-methyl-8-quinolinyl]oxy]methyl]-phenyl]sulphonyl]-N-(2-hydroxyethyl)-2(S)-pyrrolidinecarboxamide

Working analogously to Example 1, starting from the acid obtainedaccording to Preparation II and 2-aminoethanol, the expected product isobtained in the form of a white solid (Yield=93%).

M.p.=120° C.

[α]²⁷ _(D)=−31° (c=0.37; CH₃OH)

EXAMPLE 441-[[2,4-Dichloro-3-[[[4-(1H-imidazol-1-yl)-2-methyl-8-quinolinyl]oxy]methyl]-phenyl]sulphonyl]-N-(2-hydroxyethyl)-2(S)-pyrrolidinecarboxamide,hemisulphate

Working analogously to Example 2, starting from the compound obtainedaccording to Example 43 and half a molar equivalent of sulphuric acid,the expected product is obtained in the form of a white powder(Yield=98%).

M.p.=140° C.

[α]²⁷ _(D)=−24° (c=0.35; CH₃OH)

EXAMPLE 451-[[2,4-Dichloro-3-[[[4-(1H-imidazol-1-yl)-2-methyl-8-quinolinyl]oxy]methyl]-phenyl]sulphonyl]-N,N-dimethyl-2(S)-pyrrolidinecarboxamide

Working analogously to Example 1, starting from the acid obtainedaccording to Preparation II and dimethylamine dissolved in ethanol, theexpected product is obtained in the form of a white solid (Yield=69%).

M.p.=88° C.

[α]²⁷ _(D)=−8° (c=0.32; CH₃OH)

EXAMPLE 461-[[2,4-Dichloro-3-[[[4-(1H-imidazol-1-yl)-2-methyl-8-quinolinyl]oxy]methyl]-phenyl]sulphonyl]-N,N-dimethyl-2(S)-pyrrolidinecarboxamide,tartrate

Working analogously to Example 2, starting from the compound obtainedaccording to Example 45, the expected product is obtained in the form ofa yellow fine powder (Yield=80%).

M.p.=121° C.

[α]²⁴ _(D)=+34° (c=0.37; CH₃OH)

EXAMPLE 471-[[2,4-Dichloro-3-[[[4-(1H-imidazol-1-yl)-2-methyl-8-quinolinyl]oxy]methyl]-phenyl]sulphonyl]-N-[2-(4-morpholinyl)ethyl]-2(S)-pyrrolidinecarboxamide

Working analogously to Example 1, starting from the acid obtainedaccording to Preparation II and 4-(2-aminoethyl)morpholine, the expectedproduct is obtained in the form of white crystals (Yield=73%).

M.p.=100° C.

[α]²⁴ _(D)=−30° (c=0.62; CH₃OH)

EXAMPLE 481-[[2,4-Dichloro-3-[[[4-(1H-imidazol-1-yl)-2-methyl-8-quinolinyl]oxy]methyl]-phenyl]sulphonyl]-N-[2-(4-morpholinyl)ethyl]-2(S)-pyrrolidinecarboxamide,hemisulphate

Working analogously to Example 44, starting from the compound obtainedaccording to Example 47, the expected product is obtained in the form ofwhite crystals (Yield=97%).

M.p.=145° C.

[α]²⁵ _(D)=−46° (c=0.75; CH₃OH)

EXAMPLE 491-[[2,4-Dichloro-3-[[[4-(1H-imidazol-1-yl)-2-methyl-8-quinolinyl]oxy]methyl]-phenyl]sulphonyl]-N-[3-(4-morpholinyl)propyl]-2(S)-pyrrolidinecarboxamide

Working analogously to Example 1, starting from the acid obtainedaccording to Preparation II and 4-(3-aminopropyl)morpholine, theexpected product is obtained in the form of white crystals (Yield=69%).

M.p.=96° C.

[α]²⁵ _(D)=−32.5° (c=064; CH₃OH)

EXAMPLE 501-[[2,4-Dichloro-3-[[[4-(1H-imidazol-1-yl)-2-methyl-8-quinolinyl]oxy]methyl]-phenyl]sulphonyl]-N-[3-(4-morpholinyl)propyl]-2(S)-pyrrolidinecarboxamide,hemisulphate

Working analogously to Example 44, starting from the compound obtainedaccording to Example 49, the expected product is obtained in the form ofwhite crystals (Yield=98%).

M.p.=150° C.

[α]²⁵ _(D)=−46.5° (c=0.84; CH₃OH)

Preparation XXIX1-[[2,4-Dichloro-3-[[[2-methyl-4-(1H-1,2,4-triazol-1-yl)-8-quinolinyl]oxy]-methyl]phenyl]sulphonyl]-N-[[1-[2-[2-(acetoxy)ethoxy]ethyl]-4-piperidinyl]-methyl]-2(S)-pyrrolidinecarboxamide

Working analogously to Preparation XIII, starting from the compoundobtained according to Example 26, the expected product is obtained inthe form of beige crystals (Yield=60%).

M.p.=86° C.

[α]²⁶ _(D)=−37.5° (c=0.78; CH₃OH)

EXAMPLE 511-[[2,4-Dichloro-3-[[[2-methyl-4-(1H-1,2,4-triazol-1-yl)-8-quinolinyl]oxy]-methyl]phenyl]sulphonyl]-N-[[1-[2-(2-hydroxyethoxy)ethyl]-4-piperidinyl]-methyl]-2(S)-pyrrolidinecarboxamide

Working analogously to Example 11, starting from the compound obtainedaccording to Preparation XXIX, the expected product is obtained in theform of white crystals (Yield=89%).

M.p.=82° C.

[α]²⁷ _(D)=−33.2° (c=0.76; CH₃OH)

EXAMPLE 521-[[2,4-Dichloro-3-[[[2-methyl-4-(1H-1,2,4-triazol-1-yl)-8-quinolinyl]oxy]-methyl]phenyl]sulphonyl]-N-[[1-[2-(2-hydroxyethoxy)ethyl]-4-piperidinyl]-methyl]-2(S)-pyrrolidinecarboxamide,methanesulphonate

Working analogously to Example 4, starting from the compound obtainedaccording to Example 51, the expected product is obtained in the form ofpale yellow crystals (Yield=99%).

M.p.=135° C.

[α]²⁶ _(D)=−36° (c=0,70; CH₃OH)

Preparation XXXN-[[1-[[2,4-Dichloro-3-[[[4-(1H-imidazol-1-yl)-2-methyl-8-quinolinyl]oxy]-methyl]phenyl]sulphonyl]-2(S)-pyrrolidinyl]carbonyl]-β-alanine,1,1-dimethylethyl ester

Working analogously to Example 1, starting from the acid obtainedaccording to Preparation II and the t-butyl ester of β-alanine, theexpected product is obtained in the form of an ecru white solid(Yield=80%).

M.p.=68° C.

[α]²⁷ _(D)=−23° (c=0.41; CH₃OH)

EXAMPLE 53N-[[1-[[2,4-Dichloro-3-[[[4-(1H-imidazol-1-yl)-2-methyl-8-quinolinyl]oxy]-methyl]phenyl]sulphonyl]-2(S)-pyrrolidinyl]carbonyl]-β-alanine,trifluoroacetate

Working analogously to Example 13, starting from the compound obtainedaccording to Preparation XXX, the expected product is obtained in theform of a yellow fine solid (Yield=94%).

M.p.=113° C.

[α]²⁷ _(D)=−8° (c=0.44; CH₃OH)

Preparation XXXI1-[[3-(Bromomethyl)-2,4-dichlorophenyl]sulphonyl]-2(S)-(methoxymethyl)-pyrrolidine

Working analogously to Preparation VII, starting from2(S)-(methoxy-methyl)pyrrolidine, the expected product is obtained inthe form of a colourless oil (Yield=78%).

[α]²⁶ _(D)=−5.5° (c=0.73; CH₃OH)

EXAMPLE 541-[[2,4-Dichloro-3-[[[4-(1H-imidazol-1-yl)-2-methyl-8-quinolinyl)oxy]methyl]-phenyl]sulphonyl]-2(S)-(methoxymethyl)pyrrolidine

Working analogously to Preparation I, starting from8-hydroxy-4-(1H-imidazol-1-yl)-2-methylquinoline and the compoundobtained according to Preparation XXXI, the expected product is obtainedin the form of white crystals (Yield=44%).

M.p.=66° C.

[α]²⁷ _(D)=−31.5° (c=0.80; CH₃OH)

EXAMPLE 551-[[2,4-Dichloro-3-[[[4-(1H-imidazol-1-yl)-2-methyl-8-quinolinyl)oxy]methyl]-phenyl]sulphonyl]-2(S)-(methoxymethyl)pyrrolidine,methanesulphonate

Working analogously to Example 4, starting from the compound obtainedaccording to Example 54, the expected product is obtained in the form ofpale yellow crystals (Yield=99%).

M.p.=123° C.

[α]²⁶ _(D)=+21° (c=0.85; CH₃OH)

EXAMPLE 561-[[2,4-Dichloro-3-[[[2-methyl-4-(1H-pyrazol-1-yl)-8-quinolinyl)oxy]methyl]-phenyl]sulphonyl]-2(S)-(methoxymethyl)pyrrolidine

Working analogously to Example 54, starting from8-hydroxy-2-methyl-4-(1H-pyrazol-1-yl)-quinoline, the expected productis obtained in the form of white crystals (Yield=73%).

M.p.=75° C.

[α]²⁴ _(D)=+1.6° (c=0.69; CH₃OH)

EXAMPLE 571-[[2,4-Dichloro-3-[[[2-methyl-4-(1H-pyrazol-1-yl)-8-quinolinyl)oxy]methyl]-phenyl]sulphonyl]-2(S)-(methoxymethyl)pyrrolidine,methanesulphonate

Working analogously to Example 4, starting from the compound obtainedaccording to Example 56, the expected product is obtained in the form ofyellow crystals (Yield=97%).

M.p.=110° C.

[α]²⁶ _(D)=+36° (c=0.80; CH₃OH)

Preparation XXXII1-[[2,4-Dichloro-3-[[[4-(1H-imidazol-1-yl)-2-methyl-8-quinolinyl]oxy]methyl]-phenyl]sulphonyl]-D-proline,methyl ester

Working analogously to Preparation I, starting from the methyl ester ofN-[[3-(bromomethyl)-2,4-dichlorophenyl]sulphonyl]-D-proline, theexpected product is obtained in the form of a yellow solid (Yield=97%).

M.p.=74° C.

[α]²² _(D)=+10° (c=0.60; CH₃OH)

Preparation XXXIII1-[[2,4-Dichloro-3-[[[4-(1H-imidazol-1-yl)-2-methyl-8-quinolinyl]oxy]methyl]-phenyl]sulphonyl]-D-proline

Working analogously to Preparation II, starting from the compoundobtained according to Preparation XXXII, the expected product isobtained in the form of an ecru white solid (Yield=73%).

M.p.=175° C.

EXAMPLE 581-[[2,4-Dichloro-3-[[[4-(1H-imidazol-1-yl)-2-methyl-8-quinolyl]oxy]methyl]-phenyl]sulphonyl]-N-methyl-2(R)-pyrrolidinecarboxamide

Working analogously to Example 1, starting from the compound obtainedaccording to Preparation XXXIII, the expected product is obtained in theform of a white solid (Yield=83%).

M.p.=128° C.

[α]²⁵ _(D)=+25° (c=0.30; CH₃OH)

EXAMPLE 591-[[2,4-Dichloro-3-[[[4-(1H-imidazol-1-yl)-2-methyl-8-quinolyl]oxy]methyl]-phenyl]sulphonyl]-N-methyl-2(R)-pyrrolidinecarboxamide,tartrate

Working analogously to Example 2, starting from the compound obtainedaccording to Example 58, the expected product is obtained in the form ofa yellow fine solid (Yield=80%).

M.p.=114° C.

[α]²⁵ _(D)=+25° (c=0.80; CH₃OH)

EXAMPLE 601-[[2,4-Dichloro-3-[[[4-(1H-imidazol-1-yl)-2-methyl-8-quinolinyl]oxy]methyl]-phenyl]sulphonyl]-N-[3-(dimethylamino)propyl]-N-methyl-2(S)-pyrrolidine-carboxamide

Working analogously to Example 1, starting fromN,N,N′-trimethyl-1,3-propanediamine, the expected product is obtained inthe form of a white solid (Yield=64%).

M.p.=80° C.

[α]²⁵ _(D)=−16° (c=0.34; CH₃OH)

EXAMPLE 611-[[2,4-Dichloro-3-[[[4-(1H-imidazol-1-yl)-2-methyl-8-quinolinyl]oxy]methyl]-phenyl]sulphonyl]-N-[3-(dimethylamino)propyl]-N-methyl-2(S)-pyrrolidine-carboxamide,hemisulphate

Working analogously to Example 48, starting from the compound obtainedaccording to Example 60, the expected product is obtained in the form ofa white fine solid (Yield=98%).

M.p.=133° C.

[α]²⁵ _(D)=−34° (c=0.40; CH₃OH)

EXAMPLE 621-[[2,4-Dichloro-3-[[[4-(1H-imidazol-1-yl)-2-methyl-8-quinolinyl]oxy]methyl]-phenyl]sulphonyl]-N-[[1-[2-(acetoxy)ethyl]-4-piperidinyl]methyl]-2(S)-pyrrolidinecarboxamide

Working analogously to Preparation XV, starting from 2-bromoethylacetate, the expected product is obtained in the form of a beige solid(Yield=38%).

M.p.=93° C.

[α]²² _(D)=−48° (c=0.50; CHCl₃)

EXAMPLE 631-[[2,4-Dichloro-3-[[[4-(1H-imidazol-1-yl)-2-methyl-8-quinolinyl]oxy]methyl]-phenyl]sulphonyl]-N-[[1-(2-hydroxyethyl)-4-piperidinyl]methyl]-2(S)-pyrrolidinecarboxamide

Working analogously to Example 11, starting from the compound obtainedaccording to Example 62, the expected product is obtained in the form ofan ecru white solid (Yield=88%).

M.p.=104° C.

[α]¹⁸ _(D)=−53° (c=0.75; CHCl₃)

EXAMPLE 641-[[2,4-Dichloro-3-[[[4-(1H-imidazol-1-yl)-2-methyl-8-quinolinyl]oxy]methyl]-phenyl]sulphonyl]-N-[[1-(2-hydroxyethyl)-4-piperidinyl]methyl]-2(S)-pyrrolidinecarboxamide,hemisulphate

Working analogously to Example 48, starting from the compound obtainedaccording to Example 63, the expected product is obtained in the form,of a white solid (Yield=98%).

M.p.=160° C.

[α]²² _(D)=−48° (c=0.54; CH₃OH)

EXAMPLE 64 A1-[[2,4-Dichloro-3-[[[4-(1H-imidazol-1-yl)-2-methyl-8-quinolinyl]oxy]methyl]-phenyl]sulphonyl]-N-[[1-(2-hydroxyethyl)-4-piperidinyl]methyl]-2(S)-pyrrolidinecarboxamide,methanesulphonate

Working analogously to Example 4, starting from the compound obtainedaccording to Example 63, the expected product is obtained in the form ofa pale yellow solid (Yield=99%).

M.p.=127° C.

[α]²⁹ _(D)=−46° (c=0.82; CH₃OH)

Preparation XXXIV4-[[[[1-[[2,4-Dichloro-3-[[[2-methyl-4-(1H-1,2,4-triazol-1-yl)-8-quinolinyl]oxy]-methyl]phenyl]sulphonyl]-2(S)-pyrrolidinyl]carbonyl]amino]methyl]-1-piperidineaceticacid, 1,1-dimethylethyl ester

Working analogously to Preparation XVI, starting from the compoundobtained according to Example 26, the expected product is obtained inthe form of a beige solid (Yield=58%).

M.p.=50° C.

[α]²⁵ _(D)=−40° (c=0.50; CHCl₃)

EXAMPLE 654-[[[[1-[[2,4-Dichloro-3-[[[2-methyl-4-(1H-1,2,4-triazol-1-yl)-8-quinolinyl]oxy]methyl]phenyl]sulphonyl]-2(S)-pyrrolidinyl]carbonyl]amino]methyl]-1-piperidineacetic acid, bis-trifluoroacetate

Working analogously to Example 24, starting from the compound obtainedaccording to Preparation XXXIV, the expected product is obtained in theform of an ecru white powder (Yield=96%).

M.p.=142° C.

[α]¹⁹ _(D)=−37° (c=0.80; CH₃OH)

EXAMPLE 661-[[2,4-Dichloro-3-[[[4-(1H-imidazol-1-yl)-2-methyl-8-quinolinyl]oxy]methyl]-phenyl]sulphonyl]-2(S)-pyrrolidinecarboxamide

Working analogously to Example 1, starting from the acid obtainedaccording to Preparation II and ammonia introduced in gaseous form intothe reaction mixture, the expected product is obtained in the form of abeige solid (Yield=98%).

M.p.=110° C.

[α]²⁷ _(D)=−22.9° (c=0.31; CH₃OH)

EXAMPLE 671-[[2,4-Dichloro-3-[[[4-(1H-imidazol-1-yl)-2-methyl-8-quinolinyl]oxy]methyl]-phenyl]sulphonyl]-2(S)-pyrrolidinecarboxamide,tartrate

Working analogously to Example 2, starting from the compound obtainedaccording to Example 66, the expected product is obtained in the form ofa yellow solid (Yield=97%).

M.p.=124° C.

[α]²⁷ _(D)=−12.6° (c=0.41; CH₃OH)

EXAMPLE 68N-Cyclopropyl-1-[[2,4-dichloro-3-[[[4-(1H-imidazol-1-yl)-2-methyl-8-quinolinyl]oxy]methyl]phenyl]sulphonyl]-2(S)-pyrrolidinecarboxamide

Working analogously to Example 1, starting from cyclopropylamine, theexpected product is obtained in the form of an ecru white solid(Yield=87%).

M.p.=108° C.

[α]²⁴ _(D)=−19.2° (c=0.32; CH₃OH)

EXAMPLE 69N-Cyclopropyl-1-[[2,4-dichloro-3-[[[4-(1H-imidazol-1-yl)-2-methyl-8-quinolinyl]oxy]methyl]phenyl]sulphonyl]-2(S)-pyrrolidinecarboxamide,hydrochloride

Working analogously to Example 2, starting from the compound obtainedaccording to Example 68 and a solution of hydrogen chloride in methanol,the expected product is obtained in the form of a yellow powder(Yield=100%).

M.p.=160° C.

[α]²⁴ _(D)=−10.9° (c=0.36; CH₃OH)

EXAMPLE 70N-(Cyclopropylmethyl)-1-[[2,4-dichloro-3-[[[4-(1H-imidazol-1-yl)-2-methyl-8-quinolinyl]oxy]methyl]phenyl]sulphonyl]-2(S)-pyrrolidinecarboxamide

Working analogously to Example 1, starting from(aminomethyl)-cyclopropane, the expected product is obtained in the formof a white solid (Yield=98%).

M.p.=100° C.

[α]²⁴ _(D)=−22.4° (c=0.42; CH₃OH)

EXAMPLE 71N-(Cyclopropylmethyl)-1-[[2,4-dichloro-3-[[[4-(1H-imidazol-1-yl)-2-methyl-8-quinolinyl]oxy]methyl]phenyl]sulphonyl]-2(S)-pyrrolidinecarboxamide,hydrochloride

Working analogously to Example 69, starting from the compound obtainedaccording to Example 70, the expected product is obtained in the form ofa yellow powder (Yield=99%).

M.p.=155° C.

[α]²⁴ _(D)=−5.9° (c=0.33; CH₃OH)

EXAMPLE 721-[[2,4-Dichloro-3-[[[4-(1H-imidazol-1-yl)-2-methyl-8-quinolinyl]oxy]methyl]-phenyl]sulphonyl]-N-[2-(dimethylamino)ethyl]-N-methyl-2(S)-pyrrolidine-carboxamide

Working analogously to Example 1, starting fromN,N,N′-trimethyl-ethylenediamine, the expected product is obtained inthe form of a white solid (Yield=33%).

M.p.=98° C.

[α]²⁴ _(D)=−20.2° (c=0.36; CH₃OH)

EXAMPLE 731-[[2,4-Dichloro-3-[[[4-(1H-imidazol-1-yl)-2-methyl-8-quinolinyl]oxy]methyl]-phenyl]sulphonyl]-N-[2-(dimethylamino)ethyl]-N-methyl-2(S)-pyrrolidine-carboxamide,tartrate

Working analogously to Example 1, starting from the compound obtainedaccording to Example 72, the expected product is obtained in the form ofan ecru white fluffy solid (Yield=93%).

M.p.=125° C.

[α]²⁴ _(D)=−30° (c=0.43; CH₃OH)

EXAMPLE 741-[[2,4-Dichloro-3-[[[4-(1H-imidazol-1-yl)-2-methyl-8-quinolinyl]oxy]methyl]-phenyl]sulphonyl]-N-[2-(1-pyrrolidinyl)ethyl]-2(S)-pyrrolidinecarboxamide

Working analogously to Example 1, starting from1-(2-aminoethyl)-pyrrolidine, the expected product is obtained in theform of a white solid (Yield=62%).

M.p.=105° C.

[α]²⁴ _(D)=−50° (c=0.35; CH₃OH)

EXAMPLE 751-[[2,4-Dichloro-3-[[[4-(1H-imidazol-1-yl)-2-methyl-8-quinolinyl]oxy]methyl]-phenyl]sulphonyl]-N-[2-(1-pyrrolidinyl)ethyl]-2(S)-pyrrolidinecarboxamide,tartrate

Working analogously to Example 2, starting from the compound obtainedaccording to Example 74, the expected product is obtained in the form ofa yellow fine solid (Yield=97%).

M.p.=129° C.

[α]²⁴ _(D)=−30° (c=0.45; CH₃OH)

EXAMPLE 761-[[2,4-Dichloro-3-[[[4-(1H-imidazol-1-yl)-2-methyl-8-quinolinyl]oxy]methyl]-phenyl]sulphonyl]-N-[3-(1-pyrrolidinyl)propyl]-2(S)-pyrrolidinecarboxamide

Working analogously to Example 1, starting from1-(3-aminopropyl)-pyrrolidine, the expected product is obtained in theform of an ecru white solid (Yield=51%).

M.p.=120° C.

[α]²⁴ _(D)=−51° (c=0.35; CH₃OH)

EXAMPLE 771-[[2,4-Dichloro-3-[[[4-(1H-imidazol-1-yl)-2-methyl-8-quinolinyl]oxy]methyl]-phenyl]sulphonyl]-N-[3-(1-pyrrolidinyl)propyl]-2(S)-pyrrolidinecarboxamide,tartrate

Working analogously to Example 2, starting from the compound obtainedaccording to Example 76, the expected product is obtained in the form ofa yellow fine solid (Yield=95%).

M.p.=128° C.

[α]²⁴ _(D)=−32° (c=0.35; CH₃OH)

EXAMPLE 781-[[2,4-Dichloro-3-[[[4-(1H-imidazol-1-yl)-2-methyl-8-quinolinyl]oxy]methyl]-phenyl]sulphonyl]-N-[2-(1-piperidinyl)ethyl]-2(S)-pyrrolidinecarboxamide

Working analogously to Example 1, starting from1-(2-aminoethyl)-piperidine, the expected product is obtained in theform of a white solid (Yield=63%).

M.p.=108° C.

[α]²² _(D)=−35.1° (c=0.37; CH₃OH)

EXAMPLE 791-[[2,4-Dichloro-3-[[[4-(1H-imidazol-1-yl)-2-methyl-8-quinolinyl]oxy]methyl]-phenyl]sulphonyl]-N-[2-(1-piperidinyl)ethyl]-2(S)-pyrrolidinecarboxamide,tartrate

Working analogously to Example 2, starting from the compound obtainedaccording to Example 78, the expected product is obtained in the form ofa yellowish solid (Yield=98%).

M.p.=125° C.

[α]²⁰ _(D)=−43.7° (c=0.42; CH₃OH)

EXAMPLE 80N-Cyclopentyl-1-[[2,4-dichloro-3-[[[4-(1H-imidazol-1-yl)-2-methyl-8-quinolinyl]oxy]methyl]phenyl]sulphonyl]pyrrolidinecarboxamide

Working analogously to Example 1, starting from cyclopentylamine, theexpected product is obtained in the form of a white solid (Yield=86%).

M.p.=75° C.

[α]²⁵ _(D)=−17.5° (c=1.05; CH₃OH)

EXAMPLE 81N-Cyclopentyl-1-[[2,4-dichloro-3-[[[4-(1H-imidazol-1-yl)-2-methyl-8-quinolinyl]oxy]methyl]phenyl]sulphonyl]pyrrolidinecarboxamide,methanesulphonate

Working analogously to Example 6, starting from the compound obtainedaccording to Example 80, the expected product is obtained in the form ofan off-white solid (Yield=91%).

M.p.=134° C.

[α]²⁵ _(D)=+3.8° (c=0.83; DMSO)

Preparation XXXV1-[[2,4-Dichloro-3-[[[2-methyl-4-(1H-1,2,4-triazol-1-yl)-8-quinolinyl]oxy]-methyl]phenyl]sulphonyl]-L-proline,methyl ester

Working analogously to Preparation I, starting from8-hydroxy-2-methyl-4-(1H-1,2,4-triazol-1-yl)-quinoline, the expectedproduct is obtained in the form of a pale yellow solid (Yield=98%).

M.p.=130° C.

[α]²² _(D)=−35° (c=0.68; CHCl₃)

Preparation XXXVI1-[[2,4-Dichloro-3-[[[2-methyl-4-(1H-1,2,4-triazol-1-yl)-8-quinolinyl]oxy]-methyl]phenyl]sulphonyl]-L-proline

Working analogously to Preparation II, starting from the compoundobtained according to Preparation XXXV, the expected product is obtainedin the form of a pale yellow powder (Yield=75%).

M.p.=146° C.

[α]²⁴ _(D)=−5° (c=0.65; CH₃OH)

EXAMPLE 821-[[2,4-Dichloro-3-[[[2-methyl-4-(1H-1,2,4-triazol-1-yl)-8-quinolinyl]oxy]-methyl]phenyl]sulphonyl]-N-[2-(dimethylamino)ethyl]-2(S)-pyrrolidine-carboxamide

Working analogously to Example 1, starting from the compound obtainedaccording to Preparation XXXVI and N,N-dimethylethylenediamine, theexpected product is obtained in the form of white crystals (Yield=60%).

M.p.=106° C.

[α]²⁵ _(D)=−35.2° (c=0.45; CH₃OH)

EXAMPLE 831-[[2,4-Dichloro-3-[[[2-methyl-4-(1H-1,2,4-triazol-1-yl)-8-quinolinyl]oxy]-methyl]phenyl]sulphonyl]-N-[2-(dimethylamino)ethyl]-2(S)-pyrrolidine-carboxamide,tartrate

Working analogously to Example 2, starting from the compound obtainedaccording to Example 82, the expected product is obtained in the form ofwhite crystals (Yield=97%).

M.p.=128° C.

[α]²⁵ _(D)=−38.1° (c=1; CH₃OH)

EXAMPLE 841-[[2,4-Dichloro-3-[[[2-methyl-4-(1H-1,2,4-triazol-1-yl)-8-quinolinyl]oxy]-methyl]phenyl]sulphonyl]-N-[3-(dimethylamino)propyl]-2(S)-pyrrolidine-carboxamide

Working analogously to Example 82, starting fromN,N-dimethyl-1,3-propylenediamine, the expected product is obtained inthe form of a white solid (Yield=74%).

M.p.=105° C.

[α]²⁵ _(D)=−51° (c=0.75; CHCl₃)

EXAMPLE 851-[[2,4-Dichloro-3-[[[2-methyl-4-(1H-1,2,4-triazol-1-yl)-8-quinolinyl]oxy]-methyl]phenyl]sulphonyl]-N-[3-(dimethylamino)propyl]-2(S)-pyrrolidine-carboxamide,tartrate

Working analogously to Example 2, starting from the compound obtainedaccording to Example 84, the expected product is obtained in the form ofwhite crystals (Yield=99%).

M.p.=124° C.

[α]²⁵ _(D)=−42.4° (c=1; CH₃OH)

EXAMPLE 861-[[2,4-Dichloro-3-[[[2-methyl-4-(1H-1,2,4-triazol-1-yl)-8-quinolinyl]oxy]-methyl]phenyl]sulphonyl]-N-[3-(1-pyrrolidinyl)propyl]-2(S)-pyrrolidine-carboxamide

Working analogously to Example 82, starting from1-(3-aminopropyl)-pyrrolidine, the expected product is obtained in theform of white crystals (Yield=65%).

M.p.=86° C.

[α]²⁵ _(D)=−37.8° (c=0.67; CH₃OH)

EXAMPLE 871-[[2,4-Dichloro-3-[[[2-methyl-4-(1H-1,2,4-triazol-1-yl)-8-quinolinyl]oxy]-methyl]phenyl]sulphonyl]-N-[3-(1-pyrrolidinyl)propyl]-2(S)-pyrrolidine-carboxamide,methanesulphonate

Working analogously to Example 6, starting from the compound obtainedaccording to Example 86, the expected product is obtained in the form ofa white fine solid (Yield=99%).

M.p.=110° C.

[α]²⁵ _(D)=−54.6° (c=0.63; CH₃OH)

EXAMPLE 881-[[2,4-Dichloro-3-[[[4-(1H-imidazol-1-yl)-2-methyl-8-quinolinyl]oxy]methyl]-phenyl]sulphonyl]-N-[(2-pyridyl)methyl]-2(S)-pyrrolidinecarboxamide

Working analogously to Example 1, starting from2-(aminomethyl)-pyridine, the expected product is obtained in the formof a white solid (Yield=72%).

M.p.=102° C.

[α]²⁵ _(D)=−37.5° (c=0.61; CH₃OH)

EXAMPLE 891-[[2,4-Dichloro-3-[[[4-(1H-imidazol-1-yl)-2-methyl-8-quinolinyl]oxy]methyl]-phenyl]sulphonyl]-N-[(2-pyridinyl)methyl]-2(S)-pyrrolidinecarboxamide,methanesulphonate

Working analogously to Example 6, starting from the compound obtainedaccording to Example 88, the expected product is obtained in the form ofoff-white flakes (Yield=95%).

M.p.=130° C.

[α]²⁵ _(D)=−32.6° (c=0.54; CH₃OH)

EXAMPLE 901-[[2,4-Dichloro-3-[[[4-(1H-imidazol-1-yl)-2-methyl-8-quinolinyl]oxy]methyl]-phenyl]sulphonyl]-N-[(3-pyridinyl)methyl]-2(S)-pyrrolidinecarboxamide

Working analogously to Example 1, starting from3-(aminomethyl)-pyridine, the expected product is obtained in the formof a white solid (Yield=84%).

M.p.=104° C.

[α]²⁵ _(D)=−41.9° (c=0.59; CH₃OH)

EXAMPLE 911-[[2,4-Dichloro-3-[[[4-(1H-imidazol-1-yl)-2-methyl-8-quinolinyl]oxy]methyl]-phenyl]sulphonyl]-N-[(3-pyridinyl)methyl]-2(S)-pyrrolidinecarboxamide,methanesulphonate

Working analogously to Example 6, starting from the compound obtainedaccording to Example 90, the expected product is obtained in the form ofwhite crystals (Yield=99%).

M.p.=126° C.

[α]²⁵ _(D)=−35.5° (c=0.56; CH₃OH)

EXAMPLE 921-[[2,4-Dichloro-3-[[[4-(1H-imidazol-1-yl)-2-methyl-8-quinolinyl]oxy]methyl]phenyl]sulphonyl]-N-[(4-pyridinyl)methyl]-2(S)-pyrrolidinecarboxamide

Working analogously to Example 1, starting from4-(aminomethyl)-pyridine, the expected product is obtained in the formof a white solid (Yield=90%).

M.p.=114° C.

[α]²⁵ _(D)=−50.3° (c=0.51; CH₃OH)

EXAMPLE 931-[[2,4-Dichloro-3-[[[4-(1H-imidazol-1-yl)-2-methyl-8-quinolinyl]oxy]methyl]-phenyl]sulphonyl]-N-[(4-pyridinyl)methyl]-2(S)-pyrrolidinecarboxamide,tartrate

Working analogously to Example 2, starting from the compound obtainedaccording to Example 92, the expected product is obtained in the form ofa yellow solid (Yield=98%).

M.p.=128° C.

[α]²⁵ _(D)=−34.5° (c=0.49; CH₃OH)

EXAMPLE 948-[[2,6-Dichloro-3-[[2(S)-[[4-(4-pyridinyl)-1-piperazinyl]carbonyl]-1-pyrrolidinyl]sulphonyl]phenyl]methoxy]-4-(1H-imidazol-1-yl)-2-methyl-quinoline

Working analogously to Example 1, starting from1-(4-pyridinyl)-piperazine, the expected product is obtained in the formof a white solid (Yield=45%).

M.p.=136° C.

[α]²⁵ _(D)=−32.3° (c=0.46; CH₃OH)

EXAMPLE 958-[[2,6-Dichloro-3-[[2(S)-[[4-(4-pyridinyl)-1-piperazinyl]carbonyl]-1-pyrrolidinyl]sulphonyl]phenyl]methoxy]-4-(1H-imidazol-1-yl)-2-methyl-quinoline,tartrate

Working analogously to Example 2, starting from the compound obtainedaccording to Example 94, the expected product is obtained in the form ofpale yellow flakes (Yield=89%).

M.p.=146° C.

[α]²⁵ _(D)=−23.2° (c=0.52; CH₃OH)

EXAMPLE 968-[[2,6-Dichloro-3-[[2(S)-[[4-(2-pyridinyl)-1-piperazinyl]carbonyl]-1-pyrrolidinyl]sulphonyl]phenyl]methoxy]-4-(1H-imidazol-1-yl)-2-methyl-quinoline

Working analogously to Example 1, starting from1-(2-pyridinyl)-piperazine, the expected product is obtained in the formof a white solid (Yield=34%).

M.p.=108° C.

[α]²⁵ _(D)=−27.6° (c=0.4; CH₃OH)

EXAMPLE 978-[[2,6-Dichloro-3-[[2(S)-[[4-(2-pyridinyl)-1-piperazinyl]carbonyl]-1-pyrrolidinyl]sulphonyl]phenyl]methoxy]-4-(1H-imidazol-1-yl)-2-methyl-quinoline,methanesulphonate

Working analogously to Example 6, starting from the compound obtainedaccording to Example 96, the expected product is obtained in the form ofa white solid (Yield=99%).

M.p.=138° C.

[α]²⁵ _(D)=−17.3° (c=0.37; CH₃OH)

Preparation XXXVII2-[[[1-[[2,4-Dichloro-3-[[[4-(1H-imidazol-1-yl)-2-methyl-8-quinolinyl]oxy]-methyl]phenyl]sulphonyl]-2(S)-pyrrolidinyl]carbonyl](methyl)amino]ethyl]-(methyl)carbamicacid, 1,1-dimethylethyl ester

Working analogously to Example 1, starting from the t-butyl ester of[2-(methylamino)ethyl](methyl)carbamic acid, the expected product isobtained in the form of white crystals (Yield=93%).

M.p.=75° C.

[α]²⁵ _(D)=−21.4° (c=0.67; CH₃OH)

EXAMPLE 981-[[2,4-Dichloro-3-[[[4-(1H-imidazol-1-yl)-2-methyl-8-quinolinyl]oxy]methyl]-phenyl]sulphonyl]-N-methyl-N-[2-(methylamino)ethyl]-2(S)-pyrrolidine-carboxamide

Working analogously to Example 9, starting from the compound obtainedaccording to Preparation XXXVII, the expected product is obtained in theform of yellow crystals (Yield=97%).

M.p.=116° C.

[α]²⁵ _(D)=−22.6° (c=0.6; CH₃OH)

Preparation XXXVIII[3-[[[1-[[2,4-Dichloro-3-[[[4-(1H-imidazol-1-yl)-2-methyl-8-quinolinyl]oxy]-methyl]phenyl]sulphonyl]-2(S)-pyrrolidinyl]carbonyl](methyl)amino]propyl]-(methyl)carbamicacid, 1,1-dimethylethyl ester

Working analogously to Example 1, starting from the t-butyl ester of[3-(methylamino)propyl](methyl)carbamic acid, the expected product isobtained in the form of pale yellow crystals (Yield=86%).

M.p.=70° C.

[α]²⁵ _(D)=−16.4° (c=0.6; CH₃OH)

EXAMPLE 991-[[2,4-Dichloro-3-[[[4-(1H-imidazol-1-yl)-2-methyl-8-quinolinyl]oxy]methyl]-phenyl]sulphonyl]-N-methyl-N-[3-(methylamino)propyl]-2(S)-pyrrolidine-carboxamide

Working analogously to Example 9, starting from the compound obtainedaccording to Preparation XXXVIII, the expected product is obtained inthe form of yellow crystals (Yield=99%).

M.p.=125° C.

[α]²⁵ _(D)=−34.5° (c=0.54; CH₃OH)

Preparation XXXIX1-[[2,4-Dichloro-3-[[[4-(1H-imidazol-1-yl)-2-methyl-8-quinolinyl]oxy]methyl]-phenyl]sulphonyl]-N-methyl-N-[2-[[3-(acetoxy)propyl](methyl)amino]ethyl]-2(S)-pyrrolidinecarboxamide

Working analogously to Preparation XIII, starting from the compoundobtained according to Example 98 and 3-iodopropyl acetate, the expectedproduct is obtained in the form of white crystals (Yield=44%).

M.p.=75° C.

[α]²⁵ _(D)=−16.1° (c=0.6; CH₃OH)

Preparation XL1-[[2,4-Dichloro-3-[[[4-(1H-imidazol-1-yl)-2-methyl-8-quinolinyl]oxy]methyl]-phenyl]sulphonyl]-N-methyl-N-[2-[[4-(acetoxy)butyl](methyl)amino]ethyl]-2(S)-pyrrolidinecarboxamide

Working analogously to Preparation XXXIX, starting from 4-bromo-butylacetate, the expected product is obtained in the form of white crystals(Yield=55%).

M.p.=76° C.

[α]²⁵ _(D)=−14.2° (c=0.53; CH₃OH)

Preparation XLI1-[[2,4-Dichloro-3-[[[4-(1H-imidazol-1-yl)-2-methyl-8-quinolinyl]oxy]methyl]-phenyl]sulphonyl]-N-methyl-N-[3-[[3-(acetoxy)propyl](methyl)amino]propyl]-2(S)-pyrrolidinecarboxamide

Working analogously to Preparation XXXIX, starting from the compoundobtained according to Example 99, the expected product is obtained inthe form of beige crystals (Yield=73%).

M.p.=90° C.

[α]²⁵ _(D)=−28.3° (c=0.68; CH₃OH)

Preparation XLII1-[[2,4-Dichloro-3-[[[4-(1H-imidazol-1-yl)-2-methyl-8-quinolinyl]oxy]methyl]-phenyl]sulphonyl]-N-methyl-N-[3-[[4-(acetoxy)butyl](methyl)amino]propyl]-2(S)-pyrrolidinecarboxamide

Working analogously to Preparation XL, starting from the compoundobtained according to Example 99, the expected product is obtained inthe form of pale yellow crystals (Yield=69%).

M.p.=88° C.

[α]²⁵ _(D)=−29.1° (c=0.7; CH₃OH)

EXAMPLE 1001-[[2,4-Dichloro-3-[[[4-(1H-imidazol-1-yl)-2-methyl-8-quinolinyl]oxy]methyl]-phenyl]sulphonyl]-N-methyl-N-[2-[[3-(hydroxy)propyl](methyl)amino]ethyl]-2(S)-pyrrolidinecarboxamide

Working analogously to Example 11, starting from the compound obtainedaccording to Preparation XXXIX, the expected product is obtained in theform of white crystals (Yield=92%).

M.p.=98° C.

[α]²⁵ _(D)=−15.9° (c=0.6; CH₃OH)

EXAMPLE 1011-[[2,4-Dichloro-3-[[[4-(1H-imidazol-1-yl)-2-methyl-8-quinolinyl]oxy]methyl]-phenyl]sulphonyl]-N-methyl-N-[2-[[3-(hydroxy)propyl](methyl)amino]ethyl]-2(S)-pyrrolidinecarboxamide,methanesulphonate

Working analogously to Example 4, starting from the compound obtainedaccording to Example 100, the expected product is obtained in the formof white flakes (Yield=99%).

M.p.=118° C.

[α]²⁵ _(D)=−37.1° (c=0.6; CH₃OH)

EXAMPLE 1021-[[2,4-Dichloro-3-[[[4-(1H-imidazol-1-yl)-2-methyl-8-quinolinyl]oxy]methyl]-phenyl]sulphonyl]-N-methyl-N-[2-[[4-(hydroxy)butyl](methyl)amino]ethyl]-2(S)-pyrrolidinecarboxamide

Working analogously to Example 11, starting from the compound obtainedaccording to Preparation XL, the expected product is obtained in theform of white crystals (Yield=74%).

M.p.=84° C.

[α]²⁵ _(D)=−18.1° (c=0.62; CH₃OH)

EXAMPLE 1031-[[2,4-Dichloro-3-[[[4-(1H-imidazol-1-yl)-2-methyl-8-quinolinyl]oxy]methyl]-phenyl]sulphonyl]-N-methyl-N-[2-[[4-(hydroxy)butyl](methyl)amino]ethyl]-2(S)-pyrrolidinecarboxamide,methanesulphonate

Working analogously to Example 6, starting from the compound obtainedaccording to Example 102, the expected product is obtained in the formof white flakes (Yield=99%).

M.p.=120° C.

[α]²⁵ _(D)=−43.2° (c=0.65; CH₃OH)

EXAMPLE 1041-[[2,4-Dichloro-3-[[[4-(1H-imidazol-1-yl)-2-methyl-8-quinolinyl]oxy]methyl]-phenyl]sulphonyl]-N-methyl-N-[3-[[3-(hydroxy)propyl](methyl)amino]-propyl]-2(S)-pyrrolidinecarboxamide

Working analogously to Example 11, starting from the compound obtainedaccording to Preparation XLI, the expected product is obtained in theform of white crystals (Yield=84%).

M.p.=92° C.

[α]²⁵ _(D)=−18.1° (c=0.56; CH₃OH)

EXAMPLE 1051-[[2,4-Dichloro-3-[[2(L)-[[4-(2-pyridinyl)-1-piperazinyl]carbonyl]-1-pyrrolidinyl]sulphonyl]-N-methyl-N-[3-[[3-(hydroxy)propyl]-(methyl)amino]propyl]-2(S)-pyrrolidinecarboxamide,methanesulphonate

Working analogously to Example 6, starting from the compound obtainedaccording to Example 104, the expected product is obtained in the formof white flakes (Yield=99%).

M.p.=116° C.

[α]²⁵ _(D)=−49.1° (c=0.69; CH₃OH)

EXAMPLE 1061-[[2,4-Dichloro-3-[[[4-(1H-imidazol-1-yl)-2-methyl-8-quinolinyl]oxy]methyl]-phenyl]sulphonyl]-N-methyl-N-[3-[[4-(hydroxy)butyl](methyl)amino]propyl]-2(S)-pyrrolidinecarboxamide

Working analogously to Example 11, starting from the compound obtainedaccording to Preparation XLII, the expected product is obtained in theform of white crystals (Yield=77%).

M.p.=82° C.

[α]²⁵ _(D)=−22.1° (c=0.62; CH₃OH)

EXAMPLE 1071-[[2,4-Dichloro-3-[[[4-(1H-imidazol-1-yl)-2-methyl-8-quinolinyl]oxy]methyl]-phenyl]sulphonyl]-N-methyl-N-[3-[[4-(hydroxy)butyl](methyl)amino]propyl]-2(S)-pyrrolidinecarboxamide,methanesulphonate

Working analogously to Example 6, starting from the compound obtainedaccording to Example 106, the expected product is obtained in the formof white flakes (Yield=98%).

M.p.=100° C.

[α]²⁵ _(D)=−49.5° (c=0.58; CH₃OH)

EXAMPLE 1081-[[2,4-Dichloro-3-[[[4-(1H-imidazol-1-yl)-2-methyl-8-quinolinyl]oxy]methyl]-phenyl]sulphonyl]-N-[[1-(2-pyridinylmethyl)-4-piperidinyl]methyl]-2(S)-pyrrolidinecarboxamide

Working analogously to Preparation XIII, starting from2-(chloromethyl)pyridine hydrochloride, the expected product is obtainedin the form of a white solid (Yield=31%).

M.p.=100° C.

[α]²⁵ _(D)=−43.2° (c=0.4; CH₃OH)

EXAMPLE 1091-[[2,4-Dichloro-3-[[[4-(1H-imidazol-1-yl)-2-methyl-8-quinolinyl]oxy]methyl]-phenyl]sulphonyl]-N-[[1-(2-pyridinylmethyl)-4-piperidinyl]methyl]-2(S)-pyrrolidinecarboxamide,methanesulphonate

Working analogously to Example 6, starting from the compound obtainedaccording to Example 108, the expected product is obtained in the formof a white solid (Yield=90%).

M.p.=130° C.

[α]²⁵ _(D)=−44.8° (c=0.3; CH₃OH)

EXAMPLE 1101-[[2,4-Dichloro-3-[[[4-(1H-imidazol-1-yl)-2-methyl-8-quinolinyl]oxy]methyl]-phenyl]sulphonyl]-N-[[1-(3-pyridinylmethyl)-4-piperidinyl]methyl]-2(S)-pyrrolidinecarboxamide

Working analogously to Preparation XIII, starting from3-(chloromethyl)pyridine hydrochloride, the expected product is obtainedin the form of a white powder (Yield=80%).

M.p.=107° C.

[α]²⁵ _(D)=−30.7° (c=0.35; CH₃OH)

EXAMPLE 1111-[[2,4-Dichloro-3-[[[4-(1H-imidazol-1-yl)-2-methyl-8-quinolinyl]oxy]methyl]-phenyl]sulphonyl]-N-[[1-(3-pyridinylmethyl)-4-piperidinyl]methyl]-2(S)-pyrrolidinecarboxamide,methanesulphonate

Working analogously to Example 6, starting from the compound obtainedaccording to Example 110, the expected product is obtained in the formof white flakes (Yield=99%).

M.p.=141° C.

[α]²⁵ _(D)=−44.4° (c=0.36; CH₃OH)

EXAMPLE 1121-[[2,4-Dichloro-3-[[[4-(1H-imidazol-1-yl)-2-methyl-8-quinolinyl]oxy]methyl]-phenyl]sulphonyl]-N-[[1-(4-pyridinylmethyl)-4-piperidinyl]methyl]-2(S)-pyrrolidinecarboxamide

Working analogously to Preparation XIII, starting from4-(chloromethyl)pyridine hydrochloride, the expected product is obtainedin the form of a yellow solid (Yield=83%).

M.p.=113° C.

[α]²⁵ _(D)=−27.7° (c=0.39; CH₃OH)

EXAMPLE 1131-[[2,4-Dichloro-3-[[[4-(1H-imidazol-1-yl)-2-methyl-8-quinolinyl]oxy]methyl]-phenyl]sulphonyl]-N-[[1-(4-pyridinylmethyl)-4-piperidinyl]methyl]-2(S)-pyrrolidinecarboxamide,methanesulphonate

Working analogously to Example 6, starting from the compound obtainedaccording to Example 112, the expected product is obtained in the formof a white solid (Yield=92%).

M.p.=96° C.

[α]²⁵ _(D)=−39.8° (c=0.34; CH₃OH)

Preparation XLIII4-[[[[1-[[2,4-Dichloro-3-[[[4-(1H-imidazol-1-yl)-2-methyl-8-quinolinyl]oxy]-methyl]phenyl]sulphonyl]-2(S)-pyrrolidinyl]carbonyl]amino]methyl-]-1-piperidinepropanoicacid, 1,1-dimethylethyl ester

A suspension of 0.7 g (1.06×10⁻³ mol) of the compound obtained accordingto Example 9 is prepared in 20 ml de tetrahydrofuran. 0.66 g (5.1×10⁻³mol) of t-butyl acrylate is added at 50° C. and the mixture is kept at50° C. with stirring for 100 hours. The solvent is driven off underreduced pressure and the residue is purified by chromatography on silicagel eluting with the aid of a dichloromethane/methanol/ammonia(97/3/0.1; v/v/v) mixture. 0.5 g of the expected product is thusobtained in the form of a white solid (Yield=61%).

M.p.=92° C.

[α]²³ _(D)=−41° (c=0.31; CH₃OH)

EXAMPLE 1144-[[[[1-[[2,4-Dichloro-3-[[[4-(1H-imidazol-1-yl)-2-methyl-8-quinolinyl]oxy]-methyl]phenyl]sulphonyl]-2(S)-pyrrolidinyl]carbonyl]amino]methyl]-1-piperidinepropanoicacid

A solution of 0.48 g (0.61×10⁻³ mol) of the compound obtained accordingto Preparation XLIII is prepared in 30 ml of dichloromethane and, at 0°C., 66 mg (0.61×10⁻³ mol) of anisole are added and, dropwise, 10 ml oftrifluoroacetic acid. The reaction mixture is then kept with stirring atambient temperature for 20 hours, and then concentrated under reducedpressure. The residue is triturated in 10 ml of diethyl ether and thesolid product obtained is separated by filtration and then purified bychromatography on silica gel eluting with the aid of adichloromethane/methanol/ammonia (80/20/2; v/v/v) mixture. 0.2 g of theexpected product is thus obtained in the form of a white solid(Yield=45%).

M.p.=140° C.

[α]²² _(D)=−52° (c=0.35; CH₃OH)

EXAMPLE 1154-[[[[1-[[2,4-Dichloro-3-[[[4-(1H-imidazol-1-yl)-2-methyl-8-quinolinyl]oxy]-methyl]phenyl]sulphonyl]-2(S)-pyrrolidinyl]carbonyl]amino]methyl]-1-piperidinepropanoicacid, tartrate

Working analogously to Example 2, starting from the compound obtainedaccording to Example 114, the expected product is obtained in the formof a white solid (Yield=86%).

M.p.=138° C.

[α]²³ _(D)=−32° (c=0.39; CH₃OH)

Preparation XLIV4-[[[[1-[[2,4-Dichloro-3-[[[4-(1H-imidazol-1-yl)-2-methyl-8-quinolinyl]oxy]-methyl]phenyl]sulphonyl]-2(S)-pyrrolidinyl]carbonyl]amino]methyl]-1-piperidinebutanoicacid, methyl ester

Working analogously to Preparation XIII, starting from the compoundobtained according to Example 9 and methyl 4-bromobutanoate, theexpected product is obtained in the form of an ecru white solid(Yield=58%).

M.p.=98° C.

[α]²² _(D)=−40° (c=0.43; CH₃OH)

EXAMPLE 1164-[[[[1-[[2,4-Dichloro-3-[[[4-(1H-imidazol-1-yl)-2-methyl-8-quinolinyl]oxy]-methyl]phenyl]sulphonyl]-2(S)-pyrrolidinyl]carbonyl]amino]methyl]-1-piperidinebutanoicacid

A solution of 0.49 g (0.65×10⁻³ mol) of the ester obtained according toPreparation XLIV is prepared in 10 ml of dioxane and 1.3 ml of asolution of N sodium hydroxide are added. The reaction mixture is heatedat reflux for 10 hours and then concentrated under reduced pressure. Theresidue is taken up again in water and acidified to pH 4.5 with the aidof a dilute hydrochloric acid solution. The water is removed bylyophilization and the solid obtained is purified by chromatography onRP18-grafted silica gel eluting with the aid of an acetonitrile/water(2/1; v/v) mixture. 0.24 g of the expected product is thus obtained inthe form of a white solid (Yield=50%).

M.p.=178° C.

[α]²⁰ _(D)=−16° (c=0.5; CH₃OH)

EXAMPLE 1174-[[[[1-[[2,4-Dichloro-3-[[[4-(1H-imidazol-1-yl)-2-methyl-8-quinolinyl]oxy]-methyl]phenyl]sulphonyl]-2(S)-pyrrolidinyl]carbonyl]amino]methyl]-1-piperidinebutanoicacid, tartrate

Working analogously to Example 2, starting from the compound obtainedaccording to Example 116, the expected product is obtained in the formof a white solid (Yield=87%).

M.p.=158° C.

[α]²⁴ _(D)=−7° (c=0.34; CH₃OH)

Preparation XLV4-[[[[1-[[2,4-Dichloro-3-[[[4-(1H-imidazol-1-yl)-2-methyl-8-quinolinyl]oxy]-methyl]phenyl]sulphonyl]-2(S)-pyrrolidinyl]carbonyl]amino]methyl]-β-oxo-1-piperidinepropanoicacid, 1,1-dimethylethyl ester

Working analogously to Example 1, starting from the compound obtainedaccording to Example 9 and mono-t-butyl malonate, the expected productis obtained in the form of a white solid (Yield=59%).

M.p.=101° C.

[α]²⁹ _(D)=−34° (c=0.33; CH₃OH)

EXAMPLE 1184-[[[[1-[[2,4-Dichloro-3-[[[4-(1H-imidazol-1-yl)-2-methyl-8-quinolinyl]oxy]-methyl]phenyl]sulphonyl]-2(S)-pyrrolidinyl]carbonylamino]methyl]-β-oxo-1-piperidinepropanoicacid, trifluororacetate

Working analogously to Example 114, starting from the compound obtainedaccording to Preparation XLV, the expected product is obtained in theform of a yellow solid (Yield=87%).

M.p.=130° C.

[α]²² _(D)=−22° (c=0.56; CH₃OH)

EXAMPLE 1194-[[[[1-[[2,4-Dichloro-3-[[[4-(1H-imidazol-1-yl)-2-methyl-8-quinolinyl]oxy]-methyl]phenyl]sulphonyl]-2(S)-pyrrolidinyl]carbonyl]amino]methyl]-β-oxo-1-piperidinebutanoicacid

A suspension of 0.5 g (0.76×10⁻³ mol) of the compound obtained accordingto Example 9 is prepared in 15 ml of acetone and 76 mg (0.76×10⁻³ mol)of succinic anhydride are added. The reaction mixture is heated atreflux for 8 hours and the solvent is eliminated under reduced pressure.The residue is purified by chromatography on silica gel eluting with theaid of a dichloromethane/methanol/ammonia (90/10/1; v/v/v) mixture. 0.26g of the expected product is thus obtained in the form of a white solid(Yield=45%).

M.p.=125° C.

[α]²² _(D)=−33° (c=0.38; CH₃OH)

EXAMPLE 1204-[[[[1-[[2,4-Dichloro-3-[[[4-(1H-imidazol-1-yl)-2-methyl-8-quinolinyl]oxy]-methyl]phenyl]sulphonyl]-2(S)-pyrrolidinyl]carbonyl]amino]methyl]-β-oxo-1-piperidinebutanoicacid, tartrate

Working analogously to Example 2, starting from the compound obtainedaccording to Example 119, the expected product is obtained in the formof a yellow solid (Yield=75%).

M.p.=130° C.

[α]¹⁹ _(D)=−22° (c=0.50; CH₃OH)

Preparation XLVI4-[[[[1-[[2,4-Dichloro-3-[[[4-(1H-imidazol-1-yl)-2-methyl-8-quinolinyl]oxy]-methyl]phenyl]sulphonyl]-2(S)-pyrrolidinyl]carbonyl]amino]methyl]-δ-oxo-1-piperidinepentanoicacid, 1,1-dimethylethyl ester

Working analogously to Example 1, starting from the compound obtainedaccording to Example 9 and mono t-butyl glutarate, the expected productis obtained in the form of a white solid (Yield=44%).

M.p.=112° C.

[α]²² _(D)=−41° (c=0.30; CH₃OH)

EXAMPLE 1214-[[[[1-[[2,4-Dichloro-3-[[[4-(1H-imidazol-1-yl)-2-methyl-8-quinolinyl]oxy]-methyl]phenyl]sulphonyl]-2(S)-pyrrolidinyl]carbonyl]amino]methyl]-δ-oxo-1-piperidinepentanoicacid, trifluoroacetate

Working analogously to Example 13, starting from the compound obtainedaccording to Preparation XLVI, the expected product is obtained in theform of a yellow fine solid (Yield=77%).

M.p.=131° C.

[α]²³ _(D)=−15° (c=0.37; CH₃OH)

Preparation XLVIIN-[2-[[[1-[[2,4-Dichloro-3-[[[4-(1H-imidazol-1-yl)-2-methyl-8-quinolinyl]oxy]-methyl]phenyl]sulphonyl]-2(S)-pyrrolidinyl]carbonyl](methyl)amino]ethyl]-N-methylglycine,1,1-dimethylethyl ester

Working analogously to Preparation XVI, starting from the compoundobtained according to Example 98, the expected product is obtained inthe form of a white solid (Yield=67%).

M.p.=71° C.

[α]²⁵ _(D)=−20° (c=0.37; CH₃OH)

EXAMPLE 122N-[2-[[[1-[[2,4-Dichloro-3-[[[4-(1H-imidazol-1-yl)-2-methyl-8-quinolinyl]oxy]-methyl]phenyl]sulphonyl]-2(S)-pyrrolidinyl]carbonyl](methyl)amino]ethyl]-N-methylglycine,trifluoroacetate

Working analogously to Example 13, starting from the compound obtainedaccording to Preparation XLVII, the expected product is obtained in theform of a yellow solid (Yield=84%).

M.p.=120° C.

[α]²² _(D)=−29° (c=0.49; CH₃OH)

Preparation XLVIII[3-[[[1-[[2,4-Dichloro-3-[[[4-(1H-imidazol-1-yl)-2-methyl-8-quinolinyl]oxy]-methyl]phenyl]sulphonyl]-2(S)-pyrrolidinyl]carbonyl]amino]propyl](methyl)-carbamicacid, 1,1-dimethylethyl ester

Working analogously to Example 1, starting from t-butyl(3-aminopropyl)(methyl)carbamate, the expected product is obtained inthe form of a white solid (Yield=69%).

M.p.=75° C.

[α]²⁵ _(D)=−26.5° (c=0.35; CH₃OH)

EXAMPLE 1231-[[2,4-Dichloro-3-[[[4-(1H-imidazol-1-yl)-2-methyl-8-quinolinyl]oxy]methyl]-phenyl]sulphonyl]-N-[3-(methylamino)propyl]-2(S)-pyrrolidinecarboxamide,trifluoroacetate

Working analogously to Example 13, starting from the compound obtainedaccording to Preparation XLVIII, the expected product is obtained in theform of a yellow solid (Yield=99%).

M.p.=120° C.

[α]²⁴ _(D)=−49° (c=0.48; CH₃OH)

Preparation ILN-[3-[[[1-[[2,4-Dichloro-3-[[[4-(1H-imidazol-1-yl)-2-methyl-8-quinolinyl]oxy]-methyl]phenyl]sulphonyl]-2(S)-pyrrolidinyl]carbonyl](methyl)amino]propyl]-N-methylglycine,1,1-dimethylethyl ester

Working analogously to Preparation XVI, starting from the compoundobtained according to Example 99, the expected product is obtained inthe form of a white solid (Yield=73%).

M.p.=72° C.

[α]²⁵ _(D)=−12° (c=0.45; CH₃OH)

EXAMPLE 124N-[3-[[[1-[[2,4-Dichloro-3-[[[4-(1H-imidazol-1-yl)-2-methyl-8-quinolinyl]oxy]-methyl]phenyl]sulphonyl]-2(S)-pyrrolidinyl]carbonyl](methyl)amino]propyl]-N-methylglycine,bis-trifluoroacetate

Working analogously to Example 13, starting from the compound obtainedaccording to Preparation IL, the expected product is obtained in theform of a yellow solid (Yield=92%).

M.p.=110° C.

[α]²² _(D)=−34° (c=0.34; CH₃OH)

EXAMPLE 1251-[[2,4-Dichloro-3-[[[2-methyl-4-(1H-1,2,4-triazol-1-yl)-8-quinolinyl]-oxy]methyl]phenyl]sulphonyl]-N-[[1-(2-pyridinylmethyl)-4-piperidinyl]-methyl]-2(S)-pyrrolidinecarboxamide

A mixture of 0.5 g (0.563×10⁻³ mol) of the compound obtained accordingto Example 26 is prepared in 10 ml of acetonitrile. 0.39 g (2.81×10⁻³mol) of potassium carbonate and then 0.111 g (0.676×10⁻³ mol) of2-picolyl chloride (in hydrochloride form) are added. The reactionmixture is stirred at 80° C. for 45 min and then cooled and filtered.The inorganic salts are rinsed with dichloromethane which is united withthe filtrate. This solution is concentrated under reduced pressure andthe residue is purified by chromatography on silica gel eluting with theaid of a dichloromethane/methanol (9/1; v/v) mixture. The expectedproduct is thus obtained in the form of a white powder (Yield=71%).

M.p.=118° C.

[α]²⁸ _(D)=−46° (c=0.36; CHCl₃)

EXAMPLE 1261-[[2,4-Dichloro-3-[[[2-methyl-4-(1H-1,2,4-triazol-1-yl)-8-quinolinyl]oxy]-methyl]phenyl]sulphonyl]-N-[[1-(2-pyridinylmethyl)-4-piperidinyl]methyl]-2(S)-pyrrolidinecarboxamide,methanesulphonate

Working analogously to Example 6, starting from the compound obtainedaccording to Example 125, the expected product is obtained in the formof a beige solid (Yield=91%).

M.p.=139° C.

[α]²⁸ _(D)=−76° (c=0.59; CH₃OH)

EXAMPLE 1271-[[2,4-Dichloro-3-[[[4-(1H-imidazol-1-yl)-2-methyl-8-quinolinyl]oxy]methyl]-phenyl]sulphonyl]-N-[[1-(phenylmethyl)-4-piperidinyl]methyl]-2(S)-pyrrolidinecarboxamide

A mixture of 1 g (1.12×10⁻³ mol) of the compound obtained according toExample 9 is prepared in 4 ml of dimethylformamide and 100 ml ofdichloromethane. 0.787 ml (5.64×10⁻³ mol) of triethylamine is added, andthen, after having cooled the mixture to 0° C., 0.148 ml (1.24×10⁻³ mol)of benzyl bromide. The reaction mixture is kept at ambient temperaturefor 24 hours with stirring and then concentrated under reduced pressure.The residue is redissolved in ethyl acetate in the presence of water;the mixture is brought to alkaline pH (pH 9-10) with the aid of asolution of sodium hydroxide. The aqueous phase is extracted with ethylacetate and the combined organic phases are washed with water, driedover magnesium sulphate and then concentrated under reduced pressure.Purification of the crude product by chromatography on silica geleluting with the aid of a dichloromethane/methanol (95/5; v/v) mixtureallows the expected product to be obtained in the form of a white finesolid (Yield=56%).

M.p.=123° C.

[α]²⁸ _(D)=−43° (c=0.73; CH₃OH)

EXAMPLE 1281-[[2,4-Dichloro-3-[[[4-(1H-imidazol-1-yl)-2-methyl-8-quinolinyl]oxy]methyl]-phenyl]sulphonyl]-N-[[1-(phenylmethyl)-4-piperidinyl]methyl]-2(S)-pyrrolidinecarboxamide,methanesulphonate

Working analogously to Example 6, starting from the compound obtainedaccording to Example 127, the expected product is obtained in the formof a white solid (Yield=95%).

M.p.=161° C.

[α]²⁶ _(D)=−44° (c=0.63; CH₃OH)

EXAMPLE 129N-[(1-Benzoyl-4-piperidinyl)methyl]-1-[[2,4-dichloro-3-[[[4-(1H-imidazol-1-yl)-2-methyl-8-quinolinyl]oxy]methyl]phenyl]sulphonyl]-2(S)-pyrrolidine-carboxamide

Working analogously to Example 127, starting from benzoyl chloride, theexpected product is obtained in the form of a white solid (Yield=67%).

M.p.=102° C.

[α]²⁸ _(D)=−48° (c=0.66; CHCl₃)

EXAMPLE 130N-[(1-benzoyl-4-piperidinyl)methyl]-1-[[2,4-dichloro-3-[[[4-(1H-imidazol-1-yl)-2-methyl-8-quinolinyl]oxy]methyl]phenyl]sulphonyl]-2(S)-pyrrolidine-carboxamide,methanesulphonate

Working analogously to Example 6, starting from the compound obtainedaccording to Example 129, the expected product is obtained in the formof a pale yellow solid (Yield=95%).

M.p.=153° C.

[α]²⁶ _(D)=−24° (c=0.55; CH₃OH)

EXAMPLE 1311-[[2,4-Dichloro-3-[[[4-(1H-imidazol-1-yl)-2-methyl-8-quinolinyl]oxy]methyl]-phenyl]sulphonyl]-N-[[1-(4-pyridinylcarbonyl)-4-piperidinyl]methyl]-2(S)-pyrrolidinecarboxamide

Working analogously to Example 127, starting from isonicotinoyl chloridehydrochloride, the expected product is obtained in the form of a whitefine solid (Yield=34%).

M.p.=134° C.

[α]²⁸ _(D)=−56° (c=0.64; CHCl₃)

EXAMPLE 1321-[[2,4-Dichloro-3-[[[4-(1H-imidazol-1-yl)-2-methyl-8-quinolinyl]oxy]methyl]-phenyl]sulphonyl]-N-[[1-(4-pyridinylcarbonyl)-4-piperidinyl]methyl]-2(S)-pyrrolidinecarboxamide,methanesulphonate

Working analogously to Example 6, starting from the compound obtainedaccording to Example 131, the expected product is obtained in the formof a white solid (Yield=90%).

M.p.=165° C.

[α]²⁶ _(D)=−29° (c=0.48; CH₃OH)

EXAMPLE 1331-[[2,4-Dichloro-3-[[[4-(1H-imidazol-1-yl)-2-methyl-8-quinolinyl]oxy]methyl]-phenyl]sulphonyl]-N-[[1-(3-pyridinylcarbonyl)-4-piperidinyl]methyl]-2(S)-pyrrolidinecarboxamide

Working analogously to Example 127, starting from nicotinoyl chloride,the expected product is obtained in the form of a white fine solid(Yield=79%).

M.p.=109° C.

[α]²⁴ _(D)=−45° (c=0.88; CHCl₃)

EXAMPLE 1341-[[2,4-Dichloro-3-[[[4-(1H-imidazol-1-yl)-2-methyl-8-quinolinyl]oxy]methyl]-phenyl]sulphonyl]-N-[[[1-(3-pyridinylcarbonyl)-4-piperidinyl]methyl]-2(S)-pyrrolidinecarboxamide,methanesulphonate

Working analogously to Example 6, starting from the compound obtainedaccording to Example 133, the expected product is obtained in the formof a white solid (Yield=82%).

M.p.=150° C.

[α]²⁴ _(D)=−38° (c=0.59; CH₃OH)

EXAMPLE 1351-[[2,4-Dichloro-3-[[[4-(1H-imidazol-1-yl)-2-methyl-8-quinolinyl]oxy]methyl]-phenyl]sulphonyl]-N-[[1-(2-pyridinylcarbonyl)-4-piperidinyl]methyl]-2(S)-pyrrolidinecarboxamide

Working analogously to Example 1, starting from picolinic acid, theexpected product is obtained in the form of a white solid (Yield=52%).

M.p.=103° C.

[α]²⁴ _(D)=−58° (c=0.90; CHCl₃)

EXAMPLE 1361-[[2,4-Dichloro-3-[[[4-(1H-imidazol-1-yl)-2-methyl-8-quinolinyl]oxy]methyl]-phenyl]sulphonyl]-N-[[1-(2-pyridinylcarbonyl)-4-piperidinyl]methyl]-2(S)-pyrrolidinecarboxamide,methanesulphonate

Working analogously to Example 6, starting from the compound obtainedaccording to Example 135, the expected product is obtained in the formof a pale yellow solid (Yield=89%).

M.p.=152° C.

[α]²⁴ _(D)=−25° (c=0.76; CH₃OH)

Preparation L1-[[2,4-Dichloro-3-[[[2-methyl-4-(1H-1,2,4-triazol-1-yl)-2-methyl-8-quinolinyl]oxy]methyl]phenyl]sulphonyl]-L-proline,methyl ester

Working analogously to Preparation I, starting from8-hydroxy-2-methyl-4-(1H-1,2,4-triazol-1-yl)quinoline, the expectedproduct is obtained in the form of a pale yellow solid (Yield=98%).

M.p.=130° C.

[α]²² _(D)=−35° (c=0.68; CHCl₃)

Preparation LI1-[[2,4-Dichloro-3-[[[2-methyl-4-(1H-1,2,4-triazol-1-yl)-2-methyl-8-quinolinyl]oxy]methyl]phenyl]sulphonyl]-L-proline

Working analogously to Preparation II, starting from the compoundobtained according to Preparation L, the expected product is obtained inthe form of a pale yellow solid (Yield=72%).

M.p.=146° C.

[α]²⁴ _(D)=−5° (c=0.68; CH₃OH)

EXAMPLE 1371-[[2,4-Dichloro-3-[[[2-methyl-4-(1H-1,2,4-triazol-1-yl)-2-methyl-8-quinolinyl]oxy]methyl]phenyl]sulphonyl]-N-[3-(dimethylamino)propyl]-2(S)-pyrrolidinecarboxamide

Working analogously to Example 1, starting from the acid obtainedaccording to Preparation LI and N,N-dimethylpropanediamine, the expectedproduct is obtained in the form of a beige amorphous solid (Yield=74%).

M.p.=105° C.

[α]²⁴ _(D)=−51° (c=0.75; CHCl₃)

EXAMPLE 1381-[[2,4-Dichloro-3-[[[2-methyl-4-(1H-1,2,4-triazol-1-yl)-2-methyl-8-quinolinyl]oxy]methyl]phenyl]sulphonyl]-N-[3-(dimethylamino)propyl]-2(S)-pyrrolidinecarboxamide,hemisulphate

Working analogously to Example 44, starting from the compound obtainedaccording to Example 137, the expected product is obtained in the formof a pale yellow solid (Yield=98%).

M.p.=154° C.

[α]²³ _(D)=−26° (c=0.77; CH₃OH)

EXAMPLE 1391-[[2,4-Dichloro-3-[[[2-methyl-4-(1H-1,2,4-triazol-1-yl)-2-methyl-8-quinolinyl]oxy]methyl]phenyl]sulphonyl]-N-methyl-2(S)-pyrrolidine-carboxamide

Working analogously to Example 137, starting from methylaminehydrochloride, the expected product is obtained in the form of a whitesolid (Yield=60%).

M.p.=131° C.

[α]²⁸ _(D)=−37° (c=0.94; CHCl₃)

EXAMPLE 1401-[[2,4-Dichloro-3-[[[2-methyl-4-(1H-1,2,4-triazol-1-yl)-2-methyl-8-quinolinyl]oxy]methyl]phenyl]sulphonyl]-N-[[(2-pyridinyl)methyl]-2(S)-pyrrolidinecarboxamide

Working analogously to Example 137, starting from2-(aminomethyl)-pyridine, the expected product is obtained in the formof a white fine solid (Yield=85%).

M.p.=95° C.

[α]²⁸ _(D)=−31° (c=0.53; CHCl₃)

EXAMPLE 1411-[[2,4-Dichloro-3-[[[2-methyl-4-(1H-1,2,4-triazol-1-yl)-2-methyl-8-quinolinyl]oxy]methyl]phenyl]sulphonyl]-N-[(2-pyridinyl)methyl]-2(S)-pyrrolidinecarboxamide,methanesulphonate

Working analogously to Example 4, starting from the compound obtainedaccording to Example 140, the expected product is obtained in the formof a pale yellow solid (Yield=85%).

M.p.=108° C.

[α]²⁸ _(D)=−33° (c=0.52; CH₃OH)

EXAMPLE 1428-[[2,6-Dichloro-3-[[2(S)-[[4-(2-pyridinyl)-1-piperazinyl]carbonyl]-1-pyrrolidinyl]sulphonyl]phenyl]methoxy]-2-methyl-4-(1H-1,2,4-triazol-1-yl)quinoline

Working analogously to Example 137, starting from1-(2-pyridyl)-piperazine, the expected product is obtained in the formof a white powder (Yield=75%).

M.p.=108° C.

[α]²⁶ _(D)=+9° (c=0.47; CHCl₃)

EXAMPLE 1438-[[2,6-Dichloro-3-[[2(S)-[[4-(2-pyridinyl)-1-piperazinyl]carbonyl]-1-pyrrolidinyl]sulphonyl]phenyl]methoxy]-2-methyl-4-(1H-1,2,4-triazol-1-yl)-quinoline,methanesulphonate

Working analogously to Example 6, starting from the compound obtainedaccording to Example 142, the expected product is obtained in the formof a yellow solid (Yield=88%).

M.p.=160° C.

[α]²⁶ _(D)=−12° (c=0.65; CH₃OH)

EXAMPLE 1448-[[2,6-Dichloro-3-[[2(S)-(4-morpholinylcarbonyl)-1-pyrrolidinyl]sulphonyl]-phenyl]methoxy]-4-(1H-imidazol-1-yl)-2-methylquinoline

Working analogously to Example 1, starting from morpholine, the 25expected product is obtained in the form of a white solid (Yield=76%).

M.p.=50° C.

[α]²⁷ _(D)=+15° (c=0.54; CHCl₃)

EXAMPLE 1458-[[2,6-Dichloro-3-[[2(S)-(4-morpholinylcarbonyl)-1-pyrrolidinyl]sulphonyl]-phenyl]methoxy]-4-(1H-imidazol-1-yl)-2-methylquinoline,tartrate

Working analogously to Example 2, starting from the compound obtainedaccording to Example 144, the expected product is obtained in the formof a pale yellow solid (Yield=95%).

M.p.=138° C.

[α]²⁷ _(D)=−10° (c=0.72; CH₃OH)

EXAMPLE 1468-[[2,6-Dichloro-3-[[2(S)-[(4-methyl-1-piperazinyl)carbonyl]-1-pyrrolidinyl]-sulphonyl]phenyl]methoxy]-4-(1H-imidazol-1-yl)-2-methylquinoline

Working analogously to Example 1, starting from 1-methylpiperazine, theexpected product is obtained in the form of a colourless oil(Yield=34%).

[α]²⁷ _(D)=+11° (c=0.62; CHCl₃)

¹H NMR (300 MHz; DMSOd6) 8.13 (t, J=8.6 Hz, 1H); 8.09 (s, 1H); 7.80 (d,J=8.6 Hz, 1H); 7.67 (s, 1H); 7.6-7.50 (m, 3H); 7.35-7.20 (m, 2H); 5.56(s, 2H); 5.0-4.95 (m, 1H); 3.6-3.3 (m, 6H); 2.67 (s, 3H); 2.3-2.1 (m,5H); 2.16 (s, 3H); 2.0-1.80 (m, 3H).

EXAMPLE 1478-[[2,6-Dichloro-3-[[2(S)-[(4-methyl-1-piperazinyl)carbonyl]-1-pyrrolidinyl]-sulphonyl]phenyl]methoxy]-4-(1H-imidazol-1-yl)-2-methylquinoline,tartrate

Working analogously to Example 2 starting from the compound obtainedaccording to Example 146, the expected product is obtained in the formof a pale yellow solid (Yield=94%).

M.p.=138° C.

[α]²⁷ _(D)=−13° (c=0.60; CH₃OH)

EXAMPLE 1488-[[2,6-Dichloro-3-[[2(S)-[(4-phenyl-1-piperazinyl)carbonyl]-1-pyrrolidinyl]-sulphonyl]phenyl]methoxy]-4-(1H-imidazol-1-yl)-2-methylquinoline

Working analogously to Example 1, starting from 1-phenylpiperazine, theexpected product is obtained in the form of a white solid (Yield=77%).

M.p.=88° C.

[α]²⁸ _(D)=+15° (c=0.58; CHCl₃)

EXAMPLE 1498-[[2,6-Dichloro-3-[[2(S)-[(4-phenyl-1-piperazinyl)carbonyl]-1-pyrrolidinyl]-sulphonyl]phenyl]methoxy]-4-(1H-imidazol-1-yl)-2-methylquinoline,methanesulphonate

Working analogously to Example 2, starting from the compound obtainedaccording to Example 148, the expected product is obtained in the formof a pale yellow solid (Yield=93%).

M.p.=147° C.

[α]²⁸ _(D)=−3° (c=0.50; CH₃OH)

EXAMPLE 1501-[[2,4-Dichloro-3-[[[4-(1H-imidazol-1-yl)-2-methyl-8-quinolinyl]oxy]methyl]-phenyl]sulphonyl]-N-[2-(2-pyridinyl)ethyl]-2(S)-pyrrolidinecarboxamide

Working analogously to Example 1, starting from2-(2-pyridyl)-ethylamine, the expected product is obtained in the formof a white solid (Yield=87%).

M.p.=82° C.

[α]²⁵ _(D)=−29° (c=1.13; CHCl₃)

EXAMPLE 1511-[[2,4-Dichloro-3-[[[4-(1H-imidazol-1-yl)-2-methyl-8-quinolinyl]oxy]methyl]-phenyl]sulphonyl]-N-[2-(2-pyridinyl)ethyl]-2(S)-pyrrolidinecarboxamide,methanesulphonate

Working analogously to Example 6, starting from the compound obtainedaccording to Example 150, the expected product is obtained in the formof a pale yellow solid (Yield=85%).

M.p.=110° C.

[α]²⁶ _(D)=−31° (c=0.61; CH₃OH)

EXAMPLE 1521-[[2,4-Dichloro-3-[[[4-(1H-imidazol-1-yl)-2-methyl-8-quinolinyl]oxy]methyl]-phenyl]sulphonyl]-N-[2-(3-pyridinyl)ethyl]-2(S)-pyrrolidinecarboxamide

Working analogously to Example 1, starting from2-(3-pyridinyl)-ethylamine, the expected product is obtained in the formof a white solid (Yield=87%).

M.p.=117° C.

[α]²⁹ _(D)=−41° (c=0.59; CHCl₃)

EXAMPLE 1531-[[2,4-Dichloro-3-[[[4-(1H-imidazol-1-yl)-2-methyl-8-quinolinyl]oxy]methyl]-phenyl]sulphonyl]-N-[2-(3-pyridinyl)ethyl]-2(S)-pyrrolidinecarboxamide,methanesulphonate

Working analogously to Example 6, starting from the compound obtainedaccording to Example 152, the expected product is obtained in the formof a pale yellow solid (Yield=92%).

M.p.=128° C.

[α]²⁹ _(D)=−23° (c=0.74; CH₃OH)

EXAMPLE 1541-[[2,4-Dichloro-3-[[[4-(1H-imidazol-1-yl)-2-methyl-8-quinolinyl]oxy]methyl]-phenyl]sulphonyl]-N-[2-(4-pyridinyl)ethyl]-2(S)-pyrrolidinecarboxamide

Working analogously to Example 1, starting from2-(4-pyridinyl)-ethylamine, the expected product is obtained in the formof a beige solid (Yield=94%).

M.p.=120° C.

[α]²⁷ _(D)=−45° (c=0.56; CHCl₃)

EXAMPLE 1551-[[2,4-Dichloro-3-[[[4-(1H-imidazol-1-yl)-2-methyl-8-quinolinyl]oxy]methyl]-phenyl]sulphonyl]-N-[2-(4-pyridinyl)ethyl]-2(S)-pyrrolidinecarboxamide,methanesulphonate

Working analogously to Example 6, starting from the compound obtainedaccording to Example 154, the expected product is obtained in the formof a white solid (Yield=93%).

M.p.=136° C.

[α]²⁷ _(D)=−18° (c=0.76; CH₃OH)

EXAMPLE 1561-[[2,4-Dichloro-3-[[[4-(1H-imidazol-1-yl)-2-methyl-8-quinolinyl]oxy]methyl]-phenyl]sulphonyl]-N-(phenylmethyl)-2(S)-pyrrolidinecarboxamide

Working analogously to Example 1, starting from benzylamine, theexpected product is obtained in the form of a white solid (Yield=97%).

M.p.=116° C.

[α]²⁷ _(D)=−31° (c=0.77; CHCl₃)

EXAMPLE 1571-[[2,4-Dichloro-3-[[[4-(1H-imidazol-1-yl)-2-methyl-8-quinolinyl]oxy]methyl]-phenyl]sulphonyl]-N-(phenylmethyl)-2(S)-pyrrolidinecarboxamide,methane-sulphonate

Working analogously to Example 6, starting from the compound obtainedaccording to Example 156, the expected product is obtained in the formof a pale yellow solid (Yield=91%).

M.p.=135° C.

[α]²⁵ _(D)=−103° (c=0.83; CH₃OH)

Preparation LII4-[[1-[[2,4-Dichloro-3-[[[4-(1H-imidazol-1-yl)-2-methyl-8-quinolinyl]oxy]-methyl]phenyl]sulphonyl]-2(S)-pyrrolidinyl]carbonyl]-1-piperazinecarboxylicacid, 1,1-dimethylethyl ester

Working analogously to Example 1, starting from t-butyl ester of1-piperazinecarboxylic acid (N-boc-piperazine), the expected product isobtained in the form of a white solid (Yield=33%).

M.p.=98° C.

[α]²⁵ _(D)=+4° (c=0.79; CHCl₃)

EXAMPLE 1588-[[2,6-Dichloro-3-[[2(S)-(1-piperazinylcarbonyl)-1-pyrrolidinyl]sulphonyl]-phenyl]methoxy]-4-(1H-imidazol-1-yl)-2-methyl-quinoline,bis trifluoroacetate

Working analogously to Example 13, starting from the compound obtainedaccording to Preparation LII, the expected product is obtained in theform of a pale yellow solid (Yield=99%).

M.p.=143° C.

[α]¹⁹ _(D)=+22° (c=0.47; CH₃OH)

EXAMPLE 1598-[[2,6-Dichloro-3-[[2(S)-[[4-(2-pyridinylmethyl)-1-piperazinyl]carbonyl]-1-pyrrolidinyl]sulphonyl]phenyl]methoxy]-4-(1H-imidazol-1-yl)-2-methyl-quinoline

Working analogously to Example 127, starting from the compound obtainedaccording to Example 158 and 2-picolyl chloride, the expected product isobtained in the form of a yellow oil (Yield=54%).

[α]²⁰ _(D)=+11° (c=0.54; CHCl₃)

¹H NMR (250 MHz; DMSOd6) 8.5-8.45 (m, 1H); 8.2-8.05 (m, 2H); 7.85-7.70(m, 2H); 7.68-7.64 (m, 1H); 7.6-7.5 (m, 3H); 7.42 (d, J=7.8 Hz, 1H);7.35-7.20 (m, 3H); 5.56 (s, 2H); 5-4.95 (m, 1H); 3.60 (s, 2H); 3.55-3.30(m, 6H); 2.66 (s, 3H); 2.45-2.15 (m, 5H); 2-1.8 (m, 3H).

EXAMPLE 1608-[[2,6-Dichloro-3-[[2(S)-[[4-(2-pyridinylmethyl)-1-piperazinyl]carbonyl]-1-pyrrolidinyl]sulphonyl]phenyl]methoxy]-4-(1H-imidazol-1-yl)-2-methyl-quinoline,methanesulphonate

Working analogously to Example 6, starting from the compound obtainedaccording to Example 159, the expected product is obtained in the formof a pale yellow solid (Yield=91%).

M.p.=143° C.

[α]²⁶ _(D)=−12° (c=0.56; CH₃OH)

EXAMPLE 1618-[[2,6-Dichloro-3-[[2(S)-[[4-(3-pyridinylmethyl)-1-piperazinyl]carbonyl]-1-pyrrolidinyl]sulphonyl]phenyl]methoxy]-4-(1H-imidazol-1-yl)-2-methyl-quinoline

Working analogously to Example 159, starting from 3-picolyl chloride,the expected product is obtained in the form of a white solid(Yield=26%).

M.p.=102° C.

[α]²² _(D)=+12° (c=0.40; CHCl₃)

EXAMPLE 1628-[[2,6-Dichloro-3-[[2(S)-[[4-(3-pyridinylmethyl)-1-piperazinyl]carbonyl]-1-pyrrolidinyl]sulphonyl]phenyl]methoxy]-4-(1H-imidazol-1-yl)-2-methyl-quinoline,methanesulphonate

Working analogously to Example 6, starting from the compound obtainedaccording to Example 161, the expected product is obtained in the formof a pale yellow solid (Yield=95%).

M.p.=154° C.

[α]²⁶ _(D)=−8° (c=0.72; CH₃OH)

EXAMPLE 1638-[[2,6-Dichloro-3-[[2(S)-[[4-(4-pyridinylmethyl)-1-piperazinyl]carbonyl]-1-pyrrolidinyl]sulphonyl]phenyl]methoxy]-4-(1H-imidazol-1-yl)-2-methyl-quinoline

Working analogously to Example 159, starting from 4-picolyl chloride,the expected product is obtained in the form of a beige fine solid(Yield=52%).

M.p.=108° C.

[α]²² _(D)=+12° (c=0.40; CHCl₃)

EXAMPLE 1648-[[2,6-Dichloro-3-[[2(S)-[[4-(4-pyridinylmethyl)-1-piperazinyl]carbonyl]-1-pyrrolidinyl]sulphonyl]phenyl]methoxy]-4-(1H-imidazol-1-yl)-2-methyl-quinoline,methanesulphonate

Working analogously to Example 6, starting from the compound obtainedaccording to Example 163, the expected product is obtained in the formof a yellow solid (Yield=97%).

M.p.=156° C.

[α]²³ _(D)=−14° (c=0.77; CH₃OH)

Preparation LIII1-[[2,4-Dichloro-3-[[[2-methyl-4-(1H-1,2,4-triazol-1-yl)-2-methyl-8-quinolinyl]oxy]methyl]phenyl]sulphonyl]-N-[[1-[2-(acetoxy)ethyl]-4-piperidinyl]methyl]-2(S)-pyrrolidinecarboxamide

Working analogously to Preparation XIII, starting from the compoundobtained according to Example 26 and 2-bromoethyl acetate, the expectedproduct is obtained in the form of a colourless oil (Yield=31%).

[α]²⁹ _(D)=−47° (c=0.55; CHCl₃)

¹H NMR (250 MHz; DMSOd6) 9.18 (s, 1H); 8.44 (s, 1H); 8.10 (d, J=8.6 Hz,1H); 7.93 (t, J=5.4 Hz, NH); 7.81 (d, J=8.7 Hz, 1H); 7.73 (s, 1H);7.6-7.5 (m, 3H); 5.58 (s, 2H); 4.4-4.3 (m, 1H); 4.06 (t, J=6 Hz, 2H);3.6-3.5 (m, 1H); 3.45-3.30 (m, 1H); 2.95-2.75 (m, 4H); 2.69 (s, 3H);2.50-2.45 (m, 2H); 2.25-1.75 (6H); 1.99 (s, 3H); 1.55-1.45 (m, 2H);1.35-1.20 (m, 1H); 1.15-0.95 (m, 2H).

EXAMPLE 1651-[[2,4-Dichloro-3-[[[2-methyl-4-(1H-1,2,4-triazol-1-yl)-2-methyl-8-quinolinyl]oxy]methyl]phenyl]sulphonyl]-N-[[1-[(2-hydroxyethyl)-4-piperidinyl]methyl]-2(S)-pyrrolidinecarboxamide

Working analogously to Example 11, starting from the compound obtainedaccording to Preparation LIII, the expected product is obtained in theform of a white solid (Yield=90%).

M.p.=115° C.

[α]²⁹ _(D)=−43° (c=0.58; CHCl₃)

EXAMPLE 1661-[[2,4-Dichloro-3-[[[2-methyl-4-(1H-1,2,4-triazol-1-yl)-2-methyl-8-quinolinyl]oxy]methyl]phenyl]sulphonyl]-N-[[1-(2-(hydroxyethyl)-4-piperidinyl]methyl]-2(S)-pyrrolidinecarboxamide,methanesulphonate

Working analogously to Example 6, starting from the compound obtainedaccording to Example 165, the expected product is obtained in the formof a white solid (Yield=82%).

M.p.=137° C.

[α]²⁶ _(D)=−60° (c=0.14; CH₃OH)

EXAMPLE 1671-[[2,4-Dichloro-3-[[[4-(1H-imidazol-1-yl)-2-methyl-8-quinolinyl]oxy]methyl]-phenyl]sulphonyl]-N-[5-(dimethylamino)pentyl]-2(S)-pyrrolidinecarboxamide

Working analogously to Example 1, starting fromN,N-dimethyl-1,5-pentanediamine, the expected product is obtained in theform of a white solid (Yield=53%).

M.p.=85° C.

[α]²⁸ _(D)=−31° (c=0.37; CH₃OH)

EXAMPLE 1681-[[2,4-Dichloro-3-[[[4-(1H-imidazol-1-yl)-2-methyl-8-quinolinyl]oxy]methyl]-phenyl]sulphonyl]-N-[5-(dimethylamino)pentyl]-2(S)-pyrrolidinecarboxamide,tartrate

Working analogously to Example 2, starting from the compound obtainedaccording to Example 167, the expected product is obtained in the formof a white solid (Yield=97%).

M.p.=126° C.

[α]²⁸ _(D)=−31,6° (c=0.38; CH₃OH)

Preparation LIV1-[[3-(Bromomethyl)-2,4-dichlorophenyl]sulphonyl]-3(R)-pyrrolidinol

Working analogously to Preparation VII, starting from 3(R)-pyrrolidinol,the expected product is obtained in the form of white crystals(Yield=63%).

M.p.=121° C.

[α]²⁵ _(D)=+7.9° (c=0.51; CH₃OH)

EXAMPLE 1691-[[2,4-Dichloro-3-[[[4-(1H-imidazol-1-yl)-2-methyl-8-quinolinyl]oxy]methyl]-phenyl]sulphonyl]-3(R)-pyrrolidinol

Working analogously to Preparation I, starting from the compoundobtained according to Preparation LIV, the expected product is obtainedin the form of white crystals (Yield=28%).

M.p.=166° C.

[α]²⁵ _(D)=−2.1° (c=0.66; CH₃OH)

EXAMPLE 1701-[[2,4-Dichloro-3-[[[4-(1H-imidazol-1-yl)-2-methyl-8-quinolinyl]oxy]methyl]-phenyl]sulphonyl]-3(R)-pyrrolidinol,tartrate

Working analogously to Example 2, starting from the compound obtainedaccording to Example 169, the expected product is obtained in the formof a pale yellow fine solid (Yield=97%).

M.p.=162° C.

[α]²⁵ _(D)=+1.65° (c=0.59; CH₃OH)

Preparation LV1-[[3-(Bromomethyl)-2,4-dichlorophenyl]sulphonyl]-3(S)-pyrrolidinol

Working analogously to Preparation VII, starting from 3(S)-pyrrolidinol,the expected product is obtained in the form of white crystals(Yield=49%).

M.p.=120° C.

[α]²⁵ _(D)=−6° (c=0.61; CH₃OH)

EXAMPLE 1711-[[2,4-Dichloro-3-[[[4-(1H-imidazol-1-yl)-2-methyl-8-quinolinyl]oxy]methyl]-phenyl]sulphonyl]-3(S)-pyrrolidinol

Working analogously to Preparation I, starting from the compoundobtained according to Preparation LV, the expected product is obtainedin the form of white crystals (Yield=31%).

M.p.=166° C.

[α]²⁵ _(D)=+2.3° (c=0.54; CH₃OH)

EXAMPLE 1721-[[2,4-Dichloro-3-[[4-(1H-imidazol-1-yl)-2-methyl-8-quinolinyl]oxy]methyl]-phenyl]sulphonyl]-3(S)-pyrrolidinol,tartrate

Working analogously to Example 2, starting from the compound obtainedaccording to Example 171, the expected product is obtained in the formof a beige fine solid (Yield=99%).

M.p.=163° C.

[α]²⁵ _(D)=+3.45° (c=0.67; CH₃OH)

Preparation LVIN-[1-[[3-(Bromomethyl)-2,4-dichlorophenyl]sulphonyl]-3(R)-pyrrolidinyl]-acetamide

Working analogously to Preparation VII, starting fromN-[3(R)-pyrrolidinyl]acetamide, the expected product is obtained in theform of a white solid (Yield=81%).

M.p.=222° C.

[α]²⁵ _(D)=−1.3° (c=1.12; CHCl₃)

EXAMPLE 173N-[1-[[2,4-Dichloro-3-[[[4-(1H-imidazol-1-yl)-2-methyl-8-quinolinyl]oxy]-methyl]phenyl]sulphonyl]-3(R)-pyrrolidinyl]acetamide

Working analogously to Preparation I, starting from the compoundobtained according to Preparation LVI, the expected product is obtainedin the form of a white solid (Yield=69%).

M.p.=246° C.

[α]²⁵ _(D)=+26.2° (c=0.80; CH₃OH)

Preparation LVIIN-[1-[[3-(Bromomethyl)-2,4-dichlorophenyl]sulphonyl]-3(S)-pyrrolidinyl]-acetamide

Working analogously to Preparation VIII, starting fromN-[3(S)-pyrrolidinyl]acetamide, the expected product is obtained in theform of a white solid (Yield=86%).

M.p.=221° C.

[α]²⁵ _(D)=+1.7° (c=0.98; CHCl₃)

EXAMPLE 174N-[1-[[2,4-Dichloro-3-[[[4-(1H-imidazol-1-yl)-2-methyl-8-quinolinyl]oxy]-methyl]phenyl]sulphonyl]-3(S)-pyrrolidinyl]acetamide

Working analogously to Preparation I, starting from the compoundobtained according to Preparation LVII, the expected product is obtainedin the form of a white solid (Yield=69%).

M.p.=246° C.

[α]²⁵ _(D)=−26.6° (c=1.2; CH₃OH)

Preparation LVIIIN-[3-[[[1-[[2,4-Dichloro-3-[[[4-(1H-imidazol-1-yl)-2-methyl-8-quinolinyl]oxy]-methyl]phenyl]sulphonyl]-2(S)-pyrrolidinyl]carbonyl]amino]propyl]-N-methylglycine,1-1dimethylethyl ester

Working analogously to Preparation XVI, starting from the compoundobtained according to Example 123, the expected product is obtained inthe form of a white solid (Yield=67%).

M.p.=74° C.

[α]²⁴ _(D)=−33° (c=0.36; CH₃OH)

EXAMPLE 175N-[3-[[[1-[[2,4-Dichloro-3-[[[4-(1H-imidazol-1-yl)-2-methyl-8-quinolinyl]oxy]-methyl]phenyl]sulphonyl]-2(S)-pyrrolidinyl]carbonyl]amino]propyl]-N-methylglycine,bis trifluoroacetate

Working analogously to Example 13, starting from the compound obtainedaccording to Preparation LVIII, the expected product is obtained in theform of a yellow powder (Yield=78%).

M.p.=115° C.

[α]²⁵ _(D)=−31° (c=0.40; CH₃OH)

Preparation LIX1[[3-(Bromomethyl)-2,4-dichlorophenyl]sulphonyl]-2(S)-piperidinecarboxylicacid, methyl ester

A solution of 0.68 g (3.78×10⁻³ mol) of the hydrochloride of the methylester of 2(S)-piperidinecarboxylic acid is prepared in 30 ml ofacetonitrile and 1.14 g (11.4×10⁻³ mol) of potassium bicarbonatedissolved in 10 ml of water are added, and then 1.28 g (3.78×10⁻³ mol)of 3-(bromomethyl)-2,4-dichloro-benzenesulphonyl chloride. The reactionmixture is kept for 20 hours at ambient temperature with stirring andthen concentrated under reduced pressure. The residue is taken up againwith dichloromethane and this organic phase is washed with water, driedover magnesium sulphate and concentrated under reduced pressure. Thecrude product is purified by chromatography on silica gel eluting withthe aid of a toluene/ethyl acetate (95/5; v/v) mixture. 1.02 g of theexpected product are thus obtained in the form of a white solid(Yield=61%).

M.p.=91° C.

[α]²⁵ _(D)=+4° (c=0.56; CH₃OH)

Note: the expected product contains a proportion of analoguechloromethylated in position 3 which can react like the expected productduring the following step and has not been separated.

Preparation LX1[[2,4-Dichloro-3-[[[4-(1H-imidazol-1-yl)-2-methyl-8-quinolinyl]oxy]methyl]-phenyl]sulphonyl]-2(S)-piperidinecarboxylicacid, methyl ester

Working analogously to Preparation I, starting from the compoundobtained according to Preparation LIX, the expected product is obtainedin the form of an ecru white solid (Yield=72%).

M.p.=81° C.

[α]²⁵ _(D)=+13° (c=0.380; CH₃OH)

Preparation LXI1-[[2,4-Dichloro-3-[[[4-(1H-imidazol-1-yl)-2-methyl-8-quinolinyl]oxy]methyl]-phenyl]sulphonyl]-2(S)-piperidinecarboxylicacid

Working analogously to Preparation II, starting from the compoundobtained according to Preparation LX, the expected product is obtainedin the form of a white solid (Yield=73%).

M.p.=208° C.

[α]²⁶ _(D)=−5° (c=0.30; DMSO)

EXAMPLE 1761-[[2,4-Dichloro-3-[[[4-(1H-imidazol-1-yl)-2-methyl-8-quinolinyl]oxy]methyl]-phenyl]sulphonyl]-N-methyl-2(S)-piperidinecarboxamide

Working analogously to Example 1, starting from the compound obtainedaccording to Preparation LXI, the expected product is obtained in theform of a white solid (Yield=49%).

M.p.=74° C.

[α]²⁴ _(D)=+3° (c=0.30; CH₃OH)

EXAMPLE 1771-[[2,4-Dichloro-3-[[[4-(1H-imidazol-1-yl)-2-methyl-8-quinolinyl]oxy]methyl]-phenyl]sulphonyl]-N-methyl-2(S)-piperidinecarboxamide,methanesulphonate

Working analogously to Example 6, starting from the compound obtainedaccording to Example 176, the expected product is obtained in the formof a yellow fine solid (Yield=77%).

M.p.=153° C.

[α]²⁴ _(D)=+5.2° (c=0.32; CH₃OH)

Preparation LXII3-[[3-(Bromomethyl)-2,4-dichlorophenyl]sulphonyl]-4(R)-thiazolidine-carboxylicacid, methyl ester

Working analogously to Preparation LIX, starting from the methyl esterof 4(R)-thiazolidinecarboxylic acid, the expected product is obtained inthe form of a beige solid (Yield=15%).

M.p.=48-50° C.

[α]²⁴ _(D)=−40.2° (c=1.48; CH₃OH)

Preparation LXIII3-[[2,4-Dichloro-3-[[[4-(1H-imidazol-1-yl)-2-methyl-8-quinolinyl]oxy]methyl]-phenyl]sulphonyl]-4(R)-thiazolidinecarboxylicacid, methyl ester

Working analogously to Preparation I, starting from the compoundobtained according to Preparation LXII, the expected product is obtainedin the form of an off-white solid (Yield=50%).

M.p.=60° C.

[α]²⁷ _(D)=−31.4° (c=0.28; CH₃OH)

Preparation LXIV3-[[2,4-Dichloro-3-[[[4-(1H-imidazol-1-yl)-2-methyl-8-quinolinyl]oxy]methyl]-phenyl]sulphonyl]-4(R)-thiazolidinecarboxylicacid

Working analogously to Preparation II, starting from the compoundobtained according to Preparation LXIII, the expected product isobtained in the form of a beige solid (Yield=60%).

M.p.=130° C.

[α]²⁷ _(D)=−31.8° (c=0.33; DMSO)

EXAMPLE 1783-[[2,4-Dichloro-3-[[[4-(1H-imidazol-1-yl)-2-methyl-8-quinolinyl]oxy]methyl]-phenyl]sulphonyl]-N-methyl-4(R)-thiazolidinecarboxamide

Working analogously to Example 1, starting from the compound obtainedaccording to Preparation LXIV, the expected product is obtained in theform of a white solid (Yield=80%).

M.p.=120° C.

[α]²⁷ _(D)=−65.5° (c=0.36; CH₃OH)

EXAMPLE 1793-[[2,4-Dichloro-3-[[[4-(1H-imidazol-1-yl)-2-methyl-8-quinolinyl]oxy]methyl]-phenyl]sulphonyl]-N-methyl-4(R)-thiazolidinecarboxamide,methanesulphonate

Working analogously to Example 6, starting from the compound obtainedaccording to Example 178, the expected product is obtained in the formof a yellow solid (Yield=99%).

M.p.=143° C.

[α]²⁷ _(D)=−56° (c=0.33; CH₃OH)

Preparation LXV1-[3-(Bromomethyl)-2,4-dichlorophenyl]-3-pyrrolidinecarboxylic acid,methyl ester

Working analogously to Preparation LIX, starting from the methyl esterof 3-pyrrolidinecarboxylic acid, the expected product is obtained in theform of a beige powder (Yield=76%).

M.p.=94° C.

Preparation LXVI1-[[2,4-Dichloro-3-[[[4-(1H-imidazol-1-yl)-2-methyl-8-quinolinyl]oxy]methyl]-phenyl]sulphonyl]-3-pyrrolidinecarboxylicacid, methyl ester

Working analogously to Preparation LX, starting from the compoundobtained according to Preparation LXV, the expected product is obtainedin the form of an ecru white solid (Yield=84%).

M.p.=180° C.

Preparation LXVII1-[[2,4-Dichloro-3-[[[4-(1H-imidazol-1-yl)-2-methyl-8-quinolinyl]oxy]methyl]-phenyl]sulphonyl]-3-pyrrolidinecarboxylicacid

Working analogously to Preparation LXI, starting from the compoundobtained according to Preparation LXVI, the expected product is obtainedin the form of a white solid (Yield=99%).

M.p.=145° C.

EXAMPLE 1801-[[2,4-Dichloro-3-[[[4-(1H-imidazol-1-yl)-2-methyl-8-quinolinyl]oxy]methyl]-phenyl]sulphonyl]-N-methyl-3-pyrrolidinecarboxamide

Working analogously to Example 1, starting from the compound obtainedaccording to Preparation LXVII, the expected product is obtained in theform of a white solid (Yield=80%).

M.p.=108° C.

EXAMPLE 1811-[[2,4-Dichloro-3-[[[4-(1H-imidazol-1-yl)-2-methyl-8-quinolinyl]oxy]methyl]-phenyl]sulphonyl]-N-methyl-3-pyrrolidinecarboxamide,methanesulphonate

Working analogously to Example 6, starting from the compound obtainedaccording to Example 180, the expected product is obtained in the formof a yellow solid (Yield=92%).

M.p.=137° C.

Preparation LXVIII1-[[3-(Bromomethyl)-2,4-dichlorophenyl]sulphonyl]pyrrolidine

Working analogously to Preparation LIX, starting from pyrrolidine, theexpected product is obtained in the form of a white powder (Yield=94%).

M.p.=115° C.

EXAMPLE 1828-[[2,6-Dichloro-3-(1-pyrrolidinylsulphonyl)phenyl]methoxy]-4-(1H-imidazol-1-yl)-2-methylquinoline

Working analogously to Preparation I, starting from the compoundobtained according to Preparation LXVIII, the expected product isobtained in the form of a white solid (Yield=67%).

M.p.=193° C.

EXAMPLE 1838-[[2,6-Dichloro-3-(1-pyrrolidinylsulphonyl)phenyl]methoxy]-4-(1H-imidazol-1-yl)-2-methylquinoline,hydrochloride

Working analogously to Example 69, starting from the compound obtainedaccording to Example 182, the expected product is obtained in the formof a yellow powder (Yield=99%).

M.p.=142° C.

EXAMPLE 1841-[[2,4-Dichloro-3-[[[4-(1H-imidazol-1-yl)-2-methyl-8-quinolinyl]oxy]methyl]-phenyl]sulphonyl]-4(R)-hydroxy-N-methyl)-2(S)-pyrrolidinecarboxamide

Working analogously to Example 1, starting from the compound obtainedaccording to Preparation XXVII, the expected product is obtained in theform of a white solid (Yield=49%).

M.p.=134° C.

[α]²⁴ _(D)=+5° (c=0.32; CH₃OH)

EXAMPLE 1851-[[2,4-Dichloro-3-[[[4-(1H-imidazol-1-yl)-2-methyl-8-quinolinyl]oxy]methyl]-phenyl]sulphonyl]-4(R)-hydroxy-N-methyl)-2(S)-pyrrolidinecarboxamide,tartrate

Working analogously to Example 2, starting from the compound obtainedaccording to Example 184, the expected product is obtained in the formof a pale yellow fine solid (Yield=82%).

M.p.=125° C.

[α]²⁵ _(D)=+10° (c=0.40; CH₃OH)

Preparation LXIX4(R)-Methoxy-2(S)-[(methylamino)carbonyl]-1-pyrrolidinecarboxylic acid,phenylmethyl ester

Working analogously to Example 1, starting from1-(phenyl-methoxycarbonyl)-4(R)-methoxy-L-proline, the expected productis obtained in the form of a yellow solid (Yield=65%).

M.p.=45-47° C.

Preparation LXX 4(R)-Methoxy-N-methyl-2(S)-pyrrolidinecarboxamide

A solution of 1.27 g (4.34×10⁻³ mol) of the compound obtained accordingto Preparation LXIX is prepared in 100 ml of methanol and 0.13 g of 10%palladium on carbon is added. The mixture is stirred under a hydrogenatmosphere for 2 hours at atmospheric pressure, and then filtered inorder to remove the catalyst. The removal of the solvent under reducedpressure allows 0.64 g of the expected product to be obtained in theform of an oil which is used without additional purification in thefollowing step (Yield=93%)

Preparation LXXI1-[[3-(Bromomethyl)-2,4-dichlorophenyl]sulphonyl]-4(R)-methoxy-N-methyl-2(S)-pyrrolidinecarboxamide

Working analogously to Preparation VII, starting from the compoundobtained according to Preparation LXX, the expected product is obtainedin the form of a white solid (Yield=80%).

M.p.=75° C.

[α]²⁷ _(D)=+16° (c=0.31; CH₃OH)

EXAMPLE 1861-[[2,4-Dichloro-3-[[[4-(1H-imidazol-1-yl)-2-methyl-8-quinolinyl]oxy]methyl]-phenyl]sulphonyl]-4(R)-methoxy-N-methyl)-2(S)-pyrrolidinecarboxamide

Working analogously to Preparation I, starting from the compoundobtained according to Preparation LXXI, the expected product is obtainedin the form of a white solid (Yield=40%).

M.p.=93° C.

[α]²⁷ _(D)=+19° (c=0.45; CH₃OH)

EXAMPLE 1871-[[2,4-Dichloro-3-[[[4-(1H-imidazol-1-yl)-2-methyl-8-quinolinyl]oxy]methyl]-phenyl]sulphonyl]-4(R)-methoxy-N-methyl)-2(S)-pyrrolidinecarboxamide,methanesulphonate

Working analogously to Example 6, starting from the compound obtainedaccording to Example 186, the expected product is obtained in the formof a yellowish solid (Yield=86%).

M.p.=143° C.

[α]²⁷ _(D)=+17° (c=0.36; CH₃OH)

Preparation LXXII 4(E)-Ethoxy-1-(phenylmethoxycarbonyl)-L-proline, ethylester

A solution of 3 g (11.3×10⁻³ mol) of4(E)-hydroxy-1-(phenylmethoxy-carbonyl)-L-proline is prepared in 15 mlof dimethylformamide and 1.12 g (28.2×10⁻³ mol) of sodium hydride (60%in oil) are added. After 30 min with stirring at ambient temperature,2.10 ml (26×10⁻³ mol) of iodoethane are added. The mixture is kept for24 hours at ambient temperature with stirring, and then poured onto 250ml of water and extracted with ethyl acetate. The organic phase is driedover magnesium sulphate and then concentrated under reduced pressure.The residue is purified by chromatography on silica gel eluting with theaid of a toluene/ethyl acetate (95/5; v/v) mixture. 2.3 g of theexpected product are thus obtained in the form of a yellow oil(Yield=63%).

[α]²⁵ _(D)=−42.1° (c=0.42; CH₃OH)

Preparation LXXIII 4(E)-Ethoxy-1-(phenylmethoxycarbonyl)-L-proline

Working analogously to Preparation II, starting from the compoundobtained according to Preparation LXXII, the expected product isobtained in the form of a colourless oil (Yield=99%).

[α]²⁵ _(D)=−41.9° (c=0.52; CH₃OH)

Preparation LXXIII4(R)-Ethoxy-1-(phenylmethoxycarbonyl)-N-methyl-2(S)-pyrrolidine-carboxamide

Working analogously to Example 1, starting from the compound obtainedaccording to Preparation LXXII, the expected product is obtained in theform of a colourless oil (Yield=64%).

[α]²⁵ _(D)=−31.7° (c=0.35; CH₃OH)

Preparation LXXIV 4(R)-Ethoxy-N-methyl-2(S)-pyrrolidinecarboxamide

Working analogously to Preparation LXX, starting from the compoundobtained according to Preparation LXXIII, the expected product isobtained in the form of a colourless oil (Yield=97%).

[α]²⁵ _(D)=−44.2° (c=0.29; CH₃OH)

Preparation LXXV1-[[3-(Bromomethyl)-2,4-dichlorophenyl]sulphonyl]-4(R)-ethoxy-N-methyl-2(S)-pyrrolidinecarboxamide

Working analogously to Preparation VII, starting from the compoundobtained according to Preparation LXXIV, the expected product isobtained in the form of a beige solid (Yield=89%).

M.p.=122° C.

[α]²⁵ _(D)=−5.1° (c=0.25; CH₃OH)

EXAMPLE 1881-[[2,4-Dichloro-3-[[[4-(1H-imidazol-1-yl)-2-methyl-8-quinolinyl]oxy]methyl]-phenyl]sulphonyl]-4(R)-ethoxy-N-methyl-2-(S)-pyrrolidinecarboxamide

Working analogously to Preparation I, starting from the compoundobtained according to Preparation LXXV, the expected product is obtainedin the form of a white solid (Yield=34%).

M.p.=80° C.

[α]²⁵ _(D)=+19.2° (c=0.22; CH₃OH)

EXAMPLE 1891-[[2,4-Dichloro-3-[[[4-(1H-imidazol-1-yl)-2-methyl-8-quinolyl]oxy]methyl]-phenyl]sulphonyl]-4(R)-ethoxy-N-methyl-2-(S)-pyrrolidinecarboxamide,methanesulphonate

Working analogously to Example 6, starting from the compound obtainedaccording to Example 188, the expected product is obtained in the formof a pale yellow solid (Yield=92%).

M.p.=138° C.

[α]²⁵ _(D)=+21.9° (c=0.30; CH₃OH)

Preparation LXXVI 4(E)-Propoxy-1-(phenylmethoxycarbonyl)-L-proline,propyl ester

Working analogously to Preparation LXXII, starting from iodopropane, theexpected product is obtained in the form of a yellow oil (Yield=35%).

[α]²⁵ _(D)=−52.4° (c=0.56; CH₃OH)

Preparation LXXVII 4(E)-Propoxy-1-(phenylmethoxycarbonyl)-L-proline

Working analogously to Preparation II, starting from the compoundobtained according to Preparation LXXVI, the expected product isobtained in the form of a yellow oil (Yield=99%).

[α]²⁵ _(D)=−38.3° (c=0.29; CH₃OH)

Preparation LXXVIII4(R)-Propoxy-1-(phenylmethoxycarbonyl)-N-methyl-2(S)-pyrrolidine-carboxamide

Working analogously to Example 1, starting from the compound obtainedaccording to Preparation LXXVII, the expected product is obtained in theform of a yellow oil (Yield=75%).

[α]²⁵ _(D)=−33° (c=0.28; CH₃OH)

Preparation LXXIX 4(R)-Propoxy-N-methyl-2(S)-pyrrolidinecarboxamide

Working analogously to Preparation LXX, starting from the compoundobtained according to Preparation LXXVIII, the expected product isobtained in the form of a colourless oil (Yield=90%).

[α]²⁵ _(D)=−45.4° (c=0.37; CH₃OH)

Preparation LXXX1-[[3-(Bromomethyl)-2,4-dichlorophenyl]sulphonyl]-4(R)-propoxy-N-methyl-2(S)-pyrrolidinecarboxamide

Working analogously to Preparation VII, starting from the compoundobtained according to Preparation LXXIX, the expected product isobtained in the form of a beige solid (Yield=93%).

M.p.=62° C.

[α]²⁵ _(D)=−6.9° (c=0.27; CH₃OH)

EXAMPLE 1901-[[2,4-Dichloro-3-[[[4-(1H-imidazol-1-yl)-2-methyl-8-quinolyl]oxy]methyl]-phenyl]sulphonyl]-4(R)-propoxy-N-methyl-2-(S)-pyrrolidinecarboxamide

Working analogously to Preparation I, starting from the compoundobtained according to Preparation LXXX, the expected product is obtainedin the form of a white solid (Yield=31%).

M.p.=84° C.

[α]²⁵ _(D)=+25.3° (c=0.22; CH₃OH)

EXAMPLE 1911-[[2,4-Dichloro-3-[[[4-(1H-imidazol-1-yl)-2-methyl-8-quinolyl]oxy]methyl]-phenyl]sulphonyl]-4(R)-propoxy-N-methyl-2-(S)-pyrrolidinecarboxamide,methanesulphonate

Working analogously to Example 6, starting from the compound obtainedaccording to Example 190, the expected product is obtained in the formof a pale yellow solid (Yield=94%).

M.p.=141° C.

[α]²⁵ _(D)=+13.7° (c=0.30; CH₃OH)

Preparation LXXXI4(E)-(Cyclopropylmethoxy)-1-(phenylmethoxycarbonyl)-L-proline,cyclopropylmethyl ester

Working analogously to Preparation LXXII, starting frombromomethylcyclopropane, the expected product is obtained in the form ofa yellow oil (Yield=27%).

[α]²⁵ _(D)=−28.7° (c=0.33; CH₃OH)

Preparation LXXXII4(E)-(Cyclopropylmethoxy)-1-(phenylmethoxycarbonyl)-L-proline,

Working analogously to Preparation II, starting from the compoundobtained according to Preparation LXXXI, the expected product isobtained in the form of a colourless oil (Yield=98%).

[α]²⁵ _(D)=−31.1° (c=0.25; CH₃OH)

Preparation LXXXIII4(R)-(Cyclopropylmethoxy)-1-(phenylmethoxycarbonyl)-N-methyl-2(S)-pyrrolidinecarboxamide

Working analogously to Example 1, starting from the compound obtainedaccording to Preparation LXXXII, the expected product is obtained in theform of a colourless oil (Yield=74%).

[α]²⁵ _(D)=−28.8° (c=0.28; CH₃OH)

Preparation LXXXIV4(R)-(Cyclopropylmethoxy)-N-methyl-2(S)-pyrrolidinecarboxamide

Working analogously to Preparation LXX, starting from the compoundobtained according to Preparation LXXXIII, the expected product isobtained in the form of a colourless oil (Yield=82%).

[α]²⁵ _(D)=−34.2° (c=0.24; CH₃OH)

Preparation LXXXV1-[[3-(Bromomethyl)-2,4-dichlorophenyl]sulphonyl]-4(R)-(cyclopropyl-methoxy)-N-methyl-2(S)-pyrrolidinecarboxamide

Working analogously to Preparation VII, starting from the compoundobtained according to Preparation LXXXIV, the expected product isobtained in the form of a white solid (Yield=90%).

M.p.=161° C.

[α]²⁵ _(D)=−3.9° (c=0.27; CH₃OH)

EXAMPLE 1921-[[2,4-Dichloro-3-[[[4-(1H-imidazol-1-yl)-2-methyl-8-quinolyl]oxy]methyl]-phenyl]sulphonyl]-4(R)-(cyclopropylmethoxy)-N-methyl-2-(S)-pyrrolidine-carboxamide.

Working analogously to Preparation I, starting from the compoundobtained according to Preparation LXXXV, the expected product isobtained in the form of a white solid (Yield=59%).

M.p.=98° C.

[α]²⁵ _(D)=+21.2° (c=0.23; CH₃OH)

EXAMPLE 1931-[[2,4-Dichloro-3-[[[4-(1H-imidazol-1-yl)-2-methyl-8-quinolyl]oxy]methyl]-phenyl]sulphonyl]-4(R)-(cyclopropylmethoxy)-N-methyl-2-(S)-pyrrolidine-carboxamide,methanesulphonate

Working analogously to Example 6, starting from the compound obtainedaccording to Example 192, the expected product is obtained in the formof a pale yellow solid (Yield=87%).

M.p.=149° C.

[α]²⁵ _(D)=+22.9° (c=0.29; CH₃OH)

Preparation LXXXVI4(R)-(1,1-Dimethylethoxy)-1-(phenylmethoxycarbonyl)-N-methyl-2(S)-pyrrolidinecarboxamide

Working analogously to Example 1, starting from4(E)-(1,1-dimethyl-ethoxy)-1-(phenylmethoxycarbonyl)-L-proline, theexpected product is obtained in the form of a colourless oil(Yield=86%).

[α]²⁵ _(D)=−6.2° (c=0.43; CH₃OH)

Preparation LXXXVII4(R)-(1,1-Dimethylethoxy)-N-methyl-2(S)-pyrrolidinecarboxamide

Working analogously to Preparation LXX, starting from the compoundobtained according to Preparation LXXXVI, the expected product isobtained in the form of a colourless oil (Yield=99%).

[α]²⁵ _(D)=−34.8° (c=0.68; CH₃OH)

Preparation LXXXVIII1-[[3-(Bromomethyl)-2,4-dichlorophenyl]sulphonyl]-4(R)-(1,1-dimethyl-ethoxy)-N-methyl-2(S)-pyrrolidinecarboxamide

Working analogously to Preparation VII, starting from the compoundobtained according to Preparation LXXVII, the expected product isobtained in the form of a white solid (Yield=91%).

M.p.=73° C.

[α]²⁵ _(D)=−6.4° (c=0.44; CH₃OH)

EXAMPLE 1941-[[2,4-Dichloro-3-[[[4-(1H-imidazol-1-yl)-2-methyl-8-quinolyl]oxy]methyl]-phenyl]sulphonyl]-4(R)-(1,1-dimethylethoxy)-N-methyl-2-(S)-pyrrolidine-carboxamide

Working analogously to Preparation I, starting from the compoundobtained according to Preparation LXXXVIII, the expected product isobtained in the form of a white solid (Yield=65%).

M.p.=84° C.

[α]²⁵ _(D)=+19.4° (c=0.26; CH₃OH)

EXAMPLE 1951-[[2,4-Dichloro-3-[[[4-(1H-imidazol-1-yl)-2-methyl-8-quinolyl]oxy]methyl]-phenyl]sulphonyl]-4(R)-(1,1-dimethylethoxy)-N-methyl-2-(S)-pyrrolidine-carboxamide,methanesulphonate

Working analogously to Example 6, starting from the compound obtainedaccording to Example 194, the expected product is obtained in the formof a pale yellow solid (Yield=96%).

M.p.=150° C.

[α]²⁵ _(D)=+21.6° (c=0.26; CH₃OH)

Preparation LXXXIX1-[(1,1-Dimethylethoxy)carbonyl]-4(R)-(phenylmethoxy)-N-methyl-2(S)-pyrrolidinecarboxamide

Working analogously to Example 1, starting from1-[(1,1-dimethyl-ethoxy)carbonyl]-4(E)-(phenylmethoxy)-L-proline, theexpected product is obtained in the form of a colourless oil(Yield=82%).

[α]²⁵ _(D)=−13.4° (c=0.14; CH₃OH)

Preparation XC4(R)-(Phenylmethoxy)-N-methyl-2(S)-pyrrolidinecarboxamide,trifluoroacetate

Working analogously to Example 9, starting from the compound obtainedaccording to Preparation LXXXIX, the expected product is obtained in theform of a yellow solid (Yield=98%).

M.p.=54° C.

[α]²⁵ _(D)=−3.1° (c=0.37; CH₃OH)

Preparation XCI1-[[3-(Bromomethyl)-2,4-dichlorophenyl]sulphonyl]-4(R)-(phenylmethoxy)-N-methyl-2(S)-pyrrolidinecarboxamide

Working analogously to Preparation VII, starting from the compoundobtained according to Preparation XC, the expected product is obtainedin the form of a white solid (Yield=73%).

M.p.=62-64° C.

[α]²⁵ _(D)=−14.2° (c=0.37; CH₃OH)

EXAMPLE 1961-[[2,4-Dichloro-3-[[[4-(1H-imidazol-1-yl)-2-methyl-8-quinolyl]oxy]methyl]-phenyl]sulphonyl]-4(R)-(phenylmethoxy)-N-methyl-2-(S)-pyrrolidine-carboxamide

Working analogously to Preparation I, starting from the compoundobtained according to Preparation XCI, the expected product is obtainedin the form of a white solid (Yield=29%).

M.p.=100° C.

[α]²⁵ _(D)=+6.1° (c=0.29; CH₃OH)

EXAMPLE 1971-[[2,4-Dichloro-3-[[[4-(1H-imidazol-1-yl)-2-methyl-8-quinolyl]oxy]methyl]-phenyl]sulphonyl]-4(R)-(phenylmethoxy)-N-methyl-2-(S)-pyrrolidine-carboxamide,methanesulphonate

Working analogously to Example 6, starting from the compound obtainedaccording to Example 196, the expected product is obtained in the formof a white solid (Yield=96%).

M.p.=140-142° C.

[α]²⁵ _(D)=+20.1° (c=0.32; CH₃OH)

Preparation XCII2,5-Dihydro-1-[(1,1-dimethylethoxy)carbonyl]-N-methyl-1H-pyrrole-2-(S)-carboxamide

Working analogously to Example 1, starting from2,5-dihydro-1-[(1,1-dimethylethoxy)carbonyl]-1H-pyrrole-2(S)-carboxylicacid, the expected product is obtained in the form of a white solid(Yield=77%).

M.p.=47-48° C.

[α]¹⁹ _(D)=−166° (c=0.4; CH3OH)

Preparation XCIII 2,5-Dihydro-N-methyl-1H-pyrrole-2-(S)-carboxamide,trifluoroacetate

Working analogously to Example 9, starting from the compound obtainedaccording to Preparation XCII, the expected product is obtained in theform of an oil (Yield=98%).

[α]¹⁹ _(D)=−67° (c=0.50; CH₃OH)

Preparation XCIV1-[[3-(Bromomethyl)-2,4-dichlorophenyl]sulphonyl]-2,5-dihydro-N-methyl-1H-pyrrole-2(S)-carboxamide

Working analogously to Preparation VII, starting from the compoundobtained according to Preparation XCIII, the expected product isobtained in the form of a white solid (Yield=86%).

M.p.=66° C.

[α]²⁵ _(D)=−111° (c=0.43; CH₃OH)

EXAMPLE 1981-[[2,4-Dichloro-3-[[[4-(1H-imidazol-1-yl)-2-methyl-8-quinolinyl]oxy]methyl]-phenyl]sulphonyl]-2,5-dihydro-N-methyl-1H-pyrrole-2(S)-carboxamide

Working analogously to Preparation I, starting from the compoundobtained according to Preparation XCIV, the expected product is obtainedin the form of a white solid (Yield=54%).

M.p.=132° C.

[α]²⁵ _(D)=−92° (c=0.33; CH₃OH)

EXAMPLE 1991-[[2,4-Dichloro-3-[[[4-(1H-imidazol-1-yl)-2-methyl-8-quinolinyl]oxy]methyl]-phenyl]sulphonyl]-2,5-dihydro-N-methyl-1H-pyrrole-2(S)-carboxamide,methanesulphonate

Working analogously to Example 6, starting from the compound obtainedaccording to Example 198, the expected product is obtained in the formof a yellow fine solid (Yield=99%).

M.p.=139° C.

[α]²⁵ _(D)=−76° (c=0.44; CH₃OH)

Preparation XCV1-[[3-(Bromomethyl)-2,4-dichlorophenyl]sulphonyl]-2(S)-azetidinecarboxylicacid, methyl ester

Working analogously to Preparation VII, starting from methyl2(S)-azetidinecarboxylate, the expected product is obtained in the formof a white solid (Yield=33%).

M.p.=150° C.

[α]²⁸ _(D)=+6° (c=0.38; CH₃OH)

Preparation XCVI1-[[2,4-Dichloro-3-[[[4-(1H-imidazol-1-yl)-2-methyl-8-quinolinyl]oxy]methyl]-phenyl]sulphonyl]-2(S)-azetidinecarboxylicacid, methyl ester

Working analogously to Preparation I, starting from the compoundobtained according to Preparation XCV, the expected product is obtainedin the form of a white solid (Yield=77%).

M.p.=80° C.

[α]²⁸ _(D)=+73° (c=0.32; CH₃OH)

Preparation XCVII1-[[2,4-Dichloro-3-[[[4-(1H-imidazol-1-yl)-2-methyl-8-quinolinyl]oxy]methyl]-phenyl]sulphonyl]-2(S)-azetidinecarboxylicacid

Working analogously to Preparation II, starting from the compoundobtained according to Preparation XCVI, the expected product is obtainedin the form of an ecru white solid (Yield=68%).

M.p.=160° C.

[α]²⁸ _(D)=+11.6° (c=0.32; CH₃OH)

EXAMPLE 2001-[[2,4-Dichloro-3-[[[4-(1H-imidazol-1-yl)-2-methyl-8-quinolinyl]oxy]methyl]-phenyl]sulphonyl]-N-methyl-2(S)-azetidinecarboxamide

Working analogously to Example 1, starting from the compound obtainedaccording to Preparation CXVII, the expected product is obtained in theform of a beige solid (Yield=98%).

M.p.=118° C.

[α]²⁸ _(D)=−37.8° (c=0.33; CH₃OH)

EXAMPLE 2011-[[2,4-Dichloro-3-[[[4-(1H-imidazol-1-yl)-2-methyl-8-quinolinyl]oxy]methyl]-phenyl]sulphonyl]-N-methyl-2(S)-azetidinecarboxamide,methanesulphonate

Working analogously to Example 6, starting from the compound obtainedaccording to Example 200, the expected product is obtained in the formof a yellowish solid (Yield=81%).

M.p.=135° C.

[α]²⁸ _(D)=−21.1° (c=0.35; CH₃OH)

Preparation XCVIII1-[[3-(Bromomethyl)-2,4-dichlorophenyl]sulphonyl]-4(E)-phenoxy-L-proline,methyl ester

Working analogously to Example 127, starting from3-(bromomethyl)-2,4-dichlorobenzenesulphonyl chloride and the methylester of 4(trans)-phenoxy-L-proline, the expected product is obtained inthe form of a yellow oil (Yield=75%).

[α]²⁴ _(D)=−16° (c=0.55; CHCl₃)

Preparation IC1-[[2,4-Dichloro-3-[[[4-(1H-imidazol-1-yl)-2-methyl-8-quinolinyl]oxy]methyl]-phenyl]sulphonyl]-4(E)-phenoxy-L-proline,methyl ester

Working analogously to Preparation I, starting from the compoundobtained according to Preparation XCVIII, the expected product isobtained in the form of a yellow solid (Yield=75%).

M.p.=88° C.

[α]²³ _(D)=−1.36° (c=0.5; CHCl₃)

Preparation C1-[[2,4-Dichloro-3-[[[4-(1H-imidazol-1-yl)-2-methyl-8-quinolinyl]oxy]methyl]-phenyl]sulphonyl]-4(E)-phenoxy-L-proline

Working analogously to Preparation II, starting from the compoundobtained according to Preparation IC, the expected product is obtainedin the form of a beige solid (Yield=77%).

M.p.=150° C.

[α]²⁷ _(D)=+20.9° (c=0.58; DMSO)

EXAMPLE 2021-[[2,4-Dichloro-3-[[[4-(1H-imidazol-1-yl)-2-methyl-8-quinolinyl]oxy]methyl]-phenyl]sulphonyl]-N-methyl-4(R)-phenoxy-2(S)-pyrrolidinecarboxamide

Working analogously to Example 1, starting from the compound obtainedaccording to Preparation C, the expected product is obtained in the formof a white solid (Yield=37%).

M.p.=97° C.

[α]²⁷ _(D)=−2.9° (c=0.55; CH₃OH)

EXAMPLE 2031-[[2,4-Dichloro-3-[[[4-(1H-imidazol-1-yl)-2-methyl-8-quinolinyl]oxy]methyl]-phenyl]sulphonyl]-N-methyl-4(R)-phenoxy-2(S)-pyrrolidinecarboxamide,methanesulphonate

Working analogously to Example 6, starting from the compound obtainedaccording to Example 202, the expected product is obtained in the formof a white solid (Yield=92%).

M.p.=147° C.

[α]²³ _(D)=−4.8° (c=0.47; CH₃OH)

Preparation CI4(S)-Methoxy-N-methyl-1-[(phenylmethoxy)carbonyl]-2(S)-pyrrolidine-carboxamide

Working analogously to Example 1, starting from4(cis)-methoxy-1-[(phenylmethoxy)-carbonyl]-L-proline, the expectedproduct is obtained in the form of a colourless oil (Yield=76%).

[α]²⁷ _(D)=−38° (c=0.81; CH₃OH)

Preparation CII 4(S)-Methoxy-N-methyl-2(S)-pyrrolidinecarboxamide

Working analogously to Preparation LXX, starting from the compoundobtained according to Preparation CI, the expected product is obtainedin the form of a colourless oil (Yield=95%).

Preparation CIII1-[[3-(Bromomethyl)-2,4-dichlorophenyl]sulphonyl]-4(S)-methoxy-N-methyl-2(S)-pyrrolidinecarboxamide

Working analogously to Preparation XCVIII, starting from the compoundobtained according to Preparation CII, the expected product is obtainedin the form of a yellowish solid (Yield=90%).

M.p.=64° C.

[α]²⁷ _(D)=−17° (c=0.69; CHCl₃)

EXAMPLE 2041-[[2,4-Dichloro-3-[[[4-(1H-imidazol-1-yl)-2-methyl-8-quinolinyl]oxy]methyl]-phenyl]sulphonyl]-4(S)-methoxy-N-methyl-2(S)-pyrrolidinecarboxamide

Working analogously to Preparation I, starting from the compoundobtained according to Preparation CIII, the expected product is obtainedin the form of a white solid (Yield=72%).

M.p.=64° C.

[α]²³ _(D)=−22.7° (c=0.51; CHCl₃)

EXAMPLE 2051-[[2,4-Dichloro-3-[[[4-(1H-imidazol-1-yl)-2-methyl-8-quinolinyl]oxy]methyl]-phenyl]sulphonyl]-4(S)-methoxy-N-methyl-2(S)-pyrrolidinecarboxamide,methanesulphonate

Working analogously to Example 6, starting from the compound obtainedaccording to Example 204, the expected product is obtained in the formof a yellow solid (Yield=90%).

M.p.=135° C.

[α]²⁷ _(D)=−5.3° (c=0.4; CH₃OH)

EXAMPLE 2061-[[2,4-Dichloro-3-[[[2-methyl-4-(1H-1,2,4-triazol-1-yl)-2-methyl-8-quinolinyl]oxy]methyl]phenyl]sulphonyl]-4(R)-methoxy-N-methyl-2(S)-pyrrolidinecarboxamide

Working analogously to Example 186, starting from8-hydroxy-2-methyl-4-(1H-1,2,4-triazol-1-yl)quinoline, the expectedproduct is obtained in the form of a white solid (Yield=62%).

M.p.=73° C.

[α]²⁷ _(D)=+17.2° (c=0.68; CH₃OH)

EXAMPLE 2071-[[2,4-Dichloro-3-[[[2-methyl-4-(1H-1,2,4-triazol-1-yl)-2-methyl-8-quinolinyl]oxy]methyl]phenyl]sulphonyl]-4(R)-methoxy-N-methyl-2(S)-pyrrolidinecarboxamide,methanesulphonate

Working analogously to Example 6, starting from the compound obtainedaccording to Example 206, the expected product is obtained in the formof a yellow solid (Yield=87%).

M.p.=134° C.

[α]²³ _(D)=+38° (c=0.52; CH₃OH)

The activity of the products according to the invention was evaluated,according to a first aspect, as a function of their aptitude to bind tothe bradykinin B₂ receptors. It is known that the kinins, of which oneof the principal representatives is bradykinin, form a group of smallpeptides which contribute significantly to the inflammatory response andtherefore appear to be involved in the pathology of inflammatorydiseases. It is likewise known that bradykinin is amongst one of themost powerful algesic agents known. The mode of action of kinins andmore particularly of bradykinin makes a coupling of the peptides to thetwo types of receptors called B₁ and B₂ respectively take place. The B₂receptor belongs to the large family of receptors with seventransmembrane domains coupled to the G proteins and seems to be moreparticularly involved in the field of the pathologies mentioned above.This is the reason why the products of the invention, which have theproperty of being able to bind to the B₂ receptor, inhibit the bindingof bradykinin and, consequently, suppress its harmful activity. The testemployed in order to measure this property is a competitive binding teston CHO cell membranes expressing the human B₂ receptor using bradykininlabelled with tritium ([³H]-bradykinin) as ligand.

The results are expressed by the K_(i) value, as calculated according tothe recommended method with the description of the test employed anddescribed according to D. Pruneau et al., in Br. J. Pharmacol. 1998, 125p 365-372.

According to a second aspect of the control of the activity, it wasimportant to verify that the products of the invention indeed have abradykinin-antagonist character towards the B₂ receptor, that is to saythat the compound, after binding to the B₂ receptor, does not cause thesymptoms analogous to those caused by the binding of bradykinin to thesaid B₂ receptor. This antagonist character is expressed by the valuepA₂, calculated according to a biological test employed in order tomeasure the inhibition of the contraction of the isolated humanumbilical vein by the compounds according to the invention in thepresence of bradykinin. The test procedure and the method of calculationof pA₂ are described in the articles of D. Pruneau et al. published inBr. J. Pharmacol. 1998, 125, p 365-372 and J L. Paquet et al. Br. J.Pharmacol. 1999, 126 (in print).

The values obtained with certain compounds of the invention arecollected in Table I below. The values found for the K_(i) show valueslower than 1 nM, testifying to an excellent affinity of the compoundsfor the bradykinin B₂ receptor. The values found for pA₂ arerepresentative of the antagonist character of the compounds towards thebradykinin B₂ receptor.

The compounds of the present invention, because of theirbradykinin-antagonist property towards its B₂ receptor, are useful inthe treatment of pain, and in the treatment of numerous pathologiesinvolving bradykinin or its homologues. Among these pathologies areincluded septic and haemorrhagic shock, anaphylactic reactions,arthrosis, rheumatoid polyarthritis, rhinitis, asthma, inflammatorydiseases of the gastrointestinal tract (for example colitis, rectitis,Crohn's disease), pancreatitis, certain carcinomas, hereditaryangiooedema, migraine, encephalomyelitis, meningitis, cerebrovascularaccidents (especially those caused by a traumatic cerebral shock),certain neurological disorders, inflammatory vascular conditions (forexample: atherosclerosis and arthritis of the lower members), painfulconditions (for example cephalagia, dental pain, menstrual pain),premature uterine contractions, cystitis and bums. The compoundsaccording to the invention can likewise be useful for potentiatingantiviral agents.

The compounds of the present invention, which can be used in the form offree base or of their non-toxic addition salts, in combination with aphysiologically acceptable excipient, are in general prescribed in humantherapeutics at doses of approximately 1 to 1000 mg/day, in a formadministrable by the oral route, by intravenous, intramuscular orsubcutaneous injection, by the transdermal route, by means of aerosolsor by means of suppositories. These compounds are likewise administrableby the topical route, especially in gel or ointment form.

The compounds of the present invention likewise find their use in thecosmetics field for treating pathologies of the skin or of the scalp.

TABLE I Biological activity Examples K_(i) (nM) pA₂  4 0.24 10 10 1.08.5 12 0.47 8.7 23 0.45 9.1 30 0.73 8.7 32 1.4 9.1 42 77 8.3 48 32 8.550 30 8.3 61 21 8.1  64 A 0.034 9.3 73 10 8.4 75 2.8 8.3 77 6.1 8.6 8314 7.9 87 15 8.2 89 55 8.0 101  50 8.4 103  21 7.9 105  7.7 8.3 109  158.3 115  35 8.5 123  8.1 8.4 166  5.8 8.2 170  7.8 8.0 174  8.8 8.1

What is claimed is:
 1. A heterocyclic benzenesulphonamide compound offormula (I):

wherein, Het1 is a 5-membered nitrogen-containing heterocycle, Het2 is

wherein R₁ is hydrogen, hydroxyl, C₁-C₄ alkoxy, phenoxy, phenylmethoxy,—CH₂OH, cycloalkyloxy, cycloalkylalkoxy (where each cycloalkyl fragmentis C₃-C₈ and the alkoxy fragment is C₁-C₄), —NH—CO—CH₃, —CO—NH₂ or—CO—NH—CH₃, R₂ is hydrogen, —CH₂OH, —CH₂—O—CH₃, —CONR₃R₄,

wherein R₃ is hydrogen, C₁-C₃ alkyl, C₃-C₈ cycloalkyl, (C₃-C₈) cycloakyl(C₁-C₃) alkyl, phenyl, or phenylmethyl, R₄ is hydrogen, C₁-C₃ alkyl,—(CH₂)n—CH₂OH, —(CH₂)n—COOH, —(CH₂)n—CH₂—NR₅R₆,

R₅ is hydrogen, C₁-C₃ alkyl, phenyl, phenylmethyl, pyridinyl,pyridinylmethyl, pyridinylethyl, benzoyl, 4-(aminoiminomethyl)benzoyl,—(CH₂)_(m)—CH₂OH, —(CH₂)_(m)—COOH, —(CH₂)_(m)CH₂—O—(CH₂)_(m)—CH₂OH,—CO—(CH₂)_(m)—COOH, or

R₆ is hydrogen, C₁-C₃ alkyl group, or R₅ and R₆ together form, with thenitrogen atom to which they are attached, a 5- or 6-membered Nheterocycle; n=1, 2, 3 or 4; and m=1, 2 or 3; and the addition saltsthereof.
 2. A compound of formula (I) according to claim 1, wherein Het1is 1-(1H)-imidazolyl.
 3. A compound of formula (I) according to claim 1,wherein Het2 is

wherein R₃ is hydrogen or C₁-C₃ alkyl, and R₄ is C₁-C₃ alkyl,—(CH₂)n—CH₂—NR₅R₆, pyridinylmethyl, or

wherein R₅ is (CH₂)_(m)—CH₂OH, pyridinylmethyl, or4-(aminoiminomethyl)benzoyl and R₆ is methyl, or along with R₅ and thenitrogen to which they are bonded, forms a 5- or 6-membered saturatedheterocycle.
 4. A compound of formula (I) according to claim 1, whereinHet2 is

wherein R₅ is a pyridinyl group or a pyridinylmethyl group.
 5. A methodof preparing a compound of formula (I),

wherein, Het1 is a 5-membered nitrogen-containing heterocycle, Het2 is

wherein R₁ is hydrogen, hydroxyl, C₁-C₄ alkoxy, phenoxy, phenylmethoxy,—CH₂OH, cycloalkyloxy, cycloalkylalkoxy (where each cycloalkyl fragmentis C₃-C₈ and the alkoxy fragment is C₁-C₄), —NH—CO—CH₃, —CO—NH₂ or—CO—NH—CH₃, R₂ is hydrogen, —CH₂OH, —CH₂—O—CH₃, —CONR₃R₄,

wherein R₃ is hydrogen, C₁-C₃ alkyl, C₃-C₈ cycloalkyl, (C₃-C₈)cycloalkyl (C₁-C₃) alkyl, phenyl, or phenylmethyl, R₄ is hydrogen, C₁-C₃alkyl, —(CH₂)n—CH₂OH, —(CH₂)n—COOH, —(CH₂)n—CH₂—NR₅R₆,

R₅ is hydrogen, C₁-C₃ alkyl, phenyl, phenylmethyl, pyridinyl,pyridinylmethyl, pyridinylethyl, benzoyl, 4-(aminoiminomethyl)benzoyl,—(CH₂)_(m)—CH₂OH, —(CH₂)_(m)—COOH, —(CH₂)_(m)CH₂—O—(CH₂)_(m)—CH₂OH,—CO—(CH₂)_(m)—COOH, or

R₆ is hydrogen, C₁-C₃ alkyl, or, R₅ and R₆ together form, with thenitrogen to which they are attached, a 5- or 6-membered N heterocycle;n=1, 2, 3 or 4; and m=1, 2 or 3; comprising the steps of: (a) reactingan 8-hydroxyquinoline derivative of formula (II):

wherein Het1 is a five-membered nitrogen-containing heterocyclecomprising 1, 2, 3 or 4 nitrogen atoms, and wherein M is an alkalimetal, with a compound of formula (III):

wherein X is a halogen atom, and R₁ is hydrogen, OH, an alkoxy or aphenoxy, in an anhydrous solvent, at a temperature of between 0 and 50°C. for 0.5 to 10 hours, in order to obtain a compound of formula (IV):

wherein Het1 and R₁ are as defined above; (b) hydrolysing the ester ofthe compound of formula (IV) in order to obtain a compound of formula(V):

wherein Het1 and R₁ are as defined above; (c) reacting the compound offormula (V) with an amine of formula (VI): HNR₃R₄  (VI) wherein R₃ ishydrogen, or C₁-C₃ alkyl, and R₄ is hydrogen, C₁-C₃ alkyl,—(CH₂)_(n)—CH₂OH, —(CH₂)_(n)—COOR₁₁, —(CH₂)_(n)—CH₂—NR₅R₆,

wherein R₅ is C₁-C₃ alkyl —(CH₂)_(m)—CH₂OH, —(CH₂)_(m)—COOR₁₁,—(CH₂)_(m)—CH₂—O—(CH₂)_(m)—CH₂OH, or an amino-protecting group, R₆ isC₁-C₃ alkyl or an amino-protecting group, with the proviso that R₅ andR₆ are not simultaneously an amino protecting group R₁₁ is an easilyhydrolysable protecting group for the acid functionality, n=1, 2, 3 or4, and m=1, 2 or 3, in a solvent, in the presence of activators, at atemperature close to ambient temperature for 2 to 50 hours, in order toobtain a compound of formula (VII):

wherein Het1, R₁, R₃, and R₄ are as defined above; and (d) if necessary,reacting the compound of formula (VII) in order to replace each amino-or acid protecting group by a hydrogen atom, so as to obtain a compoundof formula (I):

wherein Het1, R₁, R₃ and R₄ are as defined above, with the proviso thatthe protecting groups, if present, are replaced by hydrogen atoms; (e)if necessary, reacting the compound of formula (I) thus obtained with anacid in order to obtain the corresponding acid addition salt.
 6. Amethod of preparing a heterocyclic benzenesulphonamide compound offormula (I)

wherein Het1 is a 5-membered nitrogen-containing heterocycle, Het2 is

wherein R₁ is hydrogen, hydroxyl, C₁-C₄ alkoxy, phenoxy, phenylmethoxy,—CH₂OH, cycloalkyloxy, cycloalkylalkoxy (where each cycloalkyl fragmentis C₃-C₈ and the alkoxy fragment is C₁-C₄),—NH—CO—CH₃, —CO—NH₂ or—CO—NH—CH₃, R₂ is hydrogen, —CH₂OH, —CH₂—O—CH₃, —CONR₃R₄,

wherein R₃ is hydrogen, C₁-C₃ alkyl, C₃-C₈ cycloalkyl, (C₃-C₈)cycloalkyl (C₁-C₃) alkyl, phenyl, or phenylmethyl, R₄ is hydrogen, C₁-C₃alkyl, —(CH₂)n—CH₂OH, —(CH₂)n—COOH, —(CH₂)n—CH₂—NR₅R₆,

R₅ is hydrogen, C₁-C₃ alkyl, phenyl, phenylmethyl, pyridinyl,pyridinylmethyl, pyridinylethyl, benzoyl, 4-(aminoiminomethyl)benzoyl,—(CH₂)_(m)—CH₂OH, —(CH₂)_(m)—COOH, —(CH₂)_(m)CH₂—O—(CH₂)_(m)—CH₂OH,—CO—(CH₂)_(m)—COOH, or

R₆ is hydrogen C₁-C₃ alkyl, or, R₅ and R₆ together form, with thenitrogen to which they are attached, a 5- or 6-membered N heterocycle;n=1, 2, 3 or 4; and m=1, 2 or 3; and the addition salts thereofcomprising the steps of: (a) reacting a compound of formula (I),

wherein Het1 is 1-imidazolyl, 1-pyrazolyl, or 1-(1,2,4-triazolyl), R₃ isH, or C₁-C₃ alkyl, R₄ is a group which carries a primary or secondaryamine functionality chosen from: —(CH₂)_(n)—CH₂—NHR₆ or

wherein R₆ is H or an alkyl and n is 1, 2, 3 or 4, with a halogenatedcompound chosen from the group consisting of: Y—(CH₂)_(m)—CH₂OR₁₃,Y—(CH₂)_(m)—COOR₁₁, and Y—(CH₂)_(m)—CH₂—O—(CH₂)_(m)—CH₂OR₁₃, wherein Yis a halogen, m is 1, 2 or 3 R₁₁ is an acido-protecting group, R₁₃ is aprotecting group of the alcohol functionality in a solvent, in thepresence of an alkaline agent, at a temperature close to ambienttemperature, for 5 to 20 hours, in order to obtain a compound of formula(VII):

wherein R₃ is H or C₁-C₃ alkyl, R₄ is —(CH₂)_(n)—CH₂—NR₅R₆ or

wherein R₅ is —(CH₂)_(m)—CH₂OR₁₃, —(CH₂)_(m)—COOR₁₁, or—(CH₂)_(m)—CH₂—O—(CH₂)_(m)—CH₂OR₁₃, and Het1, R₆, R₁₁ and R₁₃ are asdefined above; (b) carrying out a deprotection reaction of each alcoholor acid functionality in order to replace R₁₃ and R₁₁ by a hydrogen atomto obtain the corresponding compounds of formula (I); and (c) ifnecessary, reacting the compound of formula (I) with an inorganic ororganic acid in order to obtain the corresponding salt.
 7. A method ofpreparing a compound of formula (I),

wherein, Het1 is a 5-membered nitrogen-containing heterocycle, Het2 is

wherein R₁ is hydrogen, hydroxyl, C₁-C₄ alkoxy, phenoxy, phenylmethoxy,—CH₂OH, cycloalkyloxy, cycloalkylalkoxy (where each cycloalkyl fragmentis C₃-C₈ and the alkoxy fragment is C₁-C₄), —NH—CO—CH₃, —CO—NH₂ or—CO—NH—CH₃, R₂ is hydrogen, —CH₂OH, —CH₂—O—CH₃, —CONR₃R₄,

wherein R₃ is hydrogen, C₁-C₃ alkyl, C₃—C₈ cycloalkyl, (C₃-C₈)cycloalkyl (C₁-C₃) alkyl, phenyl, or phenylmethyl, R₄ is hydrogen, C₁-C₃alkyl, —(CH₂)n—CH₂OH, —(CH₂)n—COOH, —(CH₂)n—CH₂—NR₅R₆,

R₅ is hydrogen, C₁-C₃ alkyl, phenyl, phenylmethyl, pyridinyl,pyridinylmethyl, pyridinylethyl, benzoyl, 4-(aminoiminomethyl)benzoyl,—(CH₂)_(m)—CH₂OH, —(CH₂)_(m)—COOH, —(CH₂)_(m)CH₂—O—(CH₂)_(m)—CH₂OH,—CO—(CH₂)_(m)—COOH, or

R₆ is hydrogen C₁-C₃ alkyl, or, R₅ and R₆ together form, with thenitrogen to which they are attached, a 5- or 6-membered N heterocycle;n=1, 2, 3 or 4; and m=1, 2 or 3; comprising the steps of: (a) reactingthe acid chloride of formula (VIII):

wherein X is a halogen, with

wherein R₁ is H, OH, alkoxy, phenoxy, phenylmethoxy, CH₂OH, C₃-C₈cycloalkyloxy or cycloalkylalkoxy where the cycloalkyl fragment is C₁-C₈and the alkoxy fragment is C₁-C₄, and R₂ is —CH₂OH, —CH₂OCH₃,—CONH(CH₂)_(n)CH₂NR₅R₁₂, —CONH(CH₂)_(n)CH₂OH, —CONH(CH₂)_(n)COOR₁₁ or

wherein n=1, 2, 3 or 4, R₅ is H or alkyl, R₁₁ is an acido-protectinggroup, and R₁₂ is an amino-protecting group, in a solvent, in thepresence of a base, at a temperature close to ambient temperature, for10 to 30 hours, in order to obtain a compound of formula (IX):

 wherein Het2 is

and X, R₁, R₂, R₁₁, R₁₂ and n are as defined above; (b) reacting thecompound of formula (IX) with an 8-hydroxyquinoline derivative offormula (II):

wherein Het1 is a 5-membered nitrogen-containing heterocycle comprising1, 2, 3 or 4 nitrogen atoms, and M is an alkali metal, in an anhydroussolvent, at a temperature of between 0 and 50° C., for 0.5 to 10 hours,in order to obtain a compound of formula (X):

wherein Het1 and Het2 are as defined above; (c) if necessary, carryingout a deprotection reaction to replace R₁₁ and R₁₂ by a hydrogen atom,in order to obtain a compound of formula (I):

wherein Het1 and Het2 are as defined above, and

R₁ is as defined above, R₂ is—CH₂OH, —CH₂OCH₃, CONH(CH₂)_(n)CH₂NHR₅,—CONH(CH₂)_(n)CH₂OH, —CONH(CH₂)_(n)COOH or

n=1, 2, 3 or 4, and R₅ is H or an alkyl group; and (d) if necessary,reacting the compound of formula (I) with an acid in order to obtain thecorresponding salt.
 8. A pharmaceutical composition, comprising aphysiologically acceptable excipient and at least one compound offormula (I):

wherein, Het1 is a 5-membered nitrogen-containing heterocycle, Het2 is

wherein R₁ is hydrogen, hydroxyl, C₁-C₄ alkoxy, phenoxy, phenylmethoxy,—CH₂OH, cycloalkyloxy, cycloalkylalkoxy (where each cycloalkyl fragmentis C₃-C₈ and the alkoxy fragment is C₁-C₄), —NH—CO—CH₃, —CO—NH₂ or—CO—NH—CH₃, R₂ is hydrogen, —CH₂OH, —CH₂—O—CH₃, —CONR₃R₄,

wherein R₃ is hydrogen, C₁-C₃ alkyl, C₃-C₈ cycloalkyl, (C₃-C₈)cycloalkyl (C₁-C₃) alkyl, phenyl, or phenylmethyl, R₄ is hydrogen, C₁-C₃alkyl, —(CH₂)n—CH₂OH, —(CH₂)n—COOH, —(CH₂)n—CH₂—NR₅R₆,

wherein R₅ is hydrogen, C₁-C₃ alkyl, phenyl, phenylmethyl, pyridinyl,pyridinylmethyl, pyridinylethyl, benzoyl, 4-(aminoiminomethyl)benzoyl,—(CH₂)_(m)—CH₂OH, —(CH₂)_(m)—COOH, —(CH₂)_(m)CH₂—O—(CH₂)_(m)—CH₂OH,—CO—(CH₂)_(m)—COOH, or

R₆ is hydrogen or a C₁-C₃ alkyl group, or, R₅ and R₆ together form, withthe nitrogen to which they are attached, a 5- or 6-membered Nheterocycle; n=1, 2, 3 or 4; and m=1, 2 or 3; and the addition saltsthereof.
 9. A method of treating a pathological state in a mammalinvolving bradykinin or its homologues comprising administration of atherapeutically effective amount of a compound which is an antagonist ofa bradykinin receptor and of analogous hormones, wherein said compoundis a heterocyclic benzenesulphonamide compound of formula (I):

wherein Het1 is a 5-membered nitrogen-containing heterocycle, Het2 is

wherein R₁ is hydrogen, hydroxyl, C₁-C₄ alkoxy, phenoxy, phenylmethoxy,—CH₂OH, cycloalkyloxy, cycloalkylalkoxy (where each cycloalkyl fragmentis C₃-C₈ and the alkoxy fragment is C₁-C₄), —NH—CO—CH₃, —CO—NH₂ or—CO—NH—CH₃, R₂ is hydrogen, —CH₂OH, —CH₂—O—CH₃, —CONR₃R₄,

wherein R₃ is hydrogen, C₁-C₃ alkyl, C₃-C₈ cycloalkyl group, (C₃-C₈)cycloalkyl (C₁-C₃) alkyl, phenyl, or phenylmethyl, R₄ is hydrogen, C₁-C₃alkyl, —(CH₂)n—CH₂OH, —(CH₂)n—COOH, —(CH₂)n—CH₂—NR₅R₆,

wherein R₅ is hydrogen, C₁-C₃ alkyl, phenyl, phenylmethyl, pyridinyl,pyridinylmethyl, pyridinylethyl, benzoyl, 4-(aminoiminomethyl)benzoyl,—(CH₂)_(m)—CH₂OH, —(CH₂)_(m)—COOH, —(CH₂)_(m)CH₂—O—(CH₂)_(m)—CH₂OH,—CO—(CH₂)_(m)—COOH, or

R₆ is hydrogen C₁-C₃ alkyl, or, R₅ and R₆ together form, with thenitrogen to which they are attached, a 5- or 6-membered N heterocycle;n=1, 2, 3 or 4; and m=1, 2 or 3; and the addition salts thereof.
 10. Amethod according to claim 9, wherein said pathological state is apainful condition.
 11. A method according to claim 9, wherein saidpathological state is an inflammatory condition.
 12. A method accordingto claim 9, wherein said pathological state is traumatism caused by asevere shock.
 13. A compound of claim 1, wherein Het1 is imidazole,pyrazole, or triazole.
 14. The method of claim 5, wherein M is sodium orpotassium.
 15. The method of claim 5, wherein X is bromine.
 16. Themethod of claim 5, wherein said ester functionality is hydrolysed at atemperature of between about 0° and 40° C.
 17. The method of claim 16,wherein said temperature is between about 10° and 35° C.
 18. The methodof claim 6, wherein Y is bromine or iodine.
 19. The method of claim 6,wherein R₁₁ is t-butyl.
 20. The method of claim 7, wherein X is bromine.